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M Follen

Publications and source records attributed to M Follen.

At least 19 recordsLinked to original sources
PubMed2005

A Java application for tissue section image analysis.

The medical industry has taken advantage of Java and Java technologies over the past few years, in large part due to the language's platform-independence and object-oriented structure. As such, Java provides powerful and effective tools for developing tissue section analysis software. The background and execution of this development are discussed in this publication. Object-oriented structure allows for the creation of "Slide", "Unit", and "Cell" objects to simulate the corresponding real-world objects. Different functions may then be created to perform various tasks on these objects, thus facilitating the development of the software package as a whole. At the current time, substantial parts of the initially planned functionality have been implemented. Getafics 1.0 is fully operational and currently supports a variety of research projects; however, there are certain features of the software that currently introduce unnecessary complexity and inefficiency. In the future, we hope to include features that obviate these problems.

Cytological Techniques↗
PubMed2003

Optical systems for in vivo molecular imaging of cancer.

Progress toward a molecular characterization of cancer would have important clinical benefits; thus, there is an important need to image the molecular features of cancer in vivo. In this paper, we describe a comprehensive strategy to develop inexpensive, rugged and portable optical imaging systems for molecular imaging of cancer, which couples the development of optically active contrast agents with advances in functional genomics of cancer. We describe initial results obtained using optically active contrast agents to image the expression of three well known molecular signatures of neoplasia: including over expression of the epidermal growth factor receptor (EGFR), matrix metallo-proteases (MMPs), and oncoproteins associated with human papillomavirus (HPV) infection. At the same time, we are developing inexpensive, portable optical systems to image the morphologic and molecular signatures of neoplasia noninvasively in real time. These real-time, portable, inexpensive systems can provide tools to characterize the molecular features of cancer in vivo.

Biomarkers, Tumor↗
PubMed2002

Near real time in vivo fibre optic confocal microscopy: sub-cellular structure resolved.

We have built a fibre optic confocal reflectance microscope capable of imaging biological tissue in near real time. The measured lateral resolution is 3 micro m and axial resolution is 6 micro m. Images of epithelial cells, excised tissue biopsies, and the human lip in vivo have been obtained at 15 frames s-1. Both cell morphology and tissue architecture can be appreciated from images obtained with this microscope. This device has the potential to enable reflected light confocal imaging of internal organs for in situ detection of pathology.

Animals↗
PubMed2001

Surrogate endpoint biomarkers and their modulation in cervical chemoprevention trials.

BACKGROUND: Surrogate endpoint biomarkers (SEBs) are used as intermediate indicators of a reduction in cancer incidence in chemoprevention studies. SEBs should be expressed differentially in normal and high risk tissue; appear at a well defined stage of carcinogenesis; be studied with reasonable sensitivity, specificity, and accuracy; and be modulated in chemoprevention trials. The concept of SEBs may be useful in the trials of many new therapies. METHODS: The current review includes a comprehensive review of the literature. Many SEBs have been the subject of intense study and include quantitative histopathology and cytology, proliferation markers, regulation markers, differentiation markers, general genomic instability markers, and tissue maintenance markers. Because of the critical biologic and epidemiologic role of the human papillomavirus (HPV) in cervical carcinogenesis, the relation between these markers and HPV should be considered. In addition, biomarkers of HPV infection and its regression should be sought. RESULTS: Several chemoprevention trials have been published that have included the use of SEBs. The biomarkers that appear most promising in these clinical trials can be measured quantitatively and reproducibly: quantitative histology and cytology, proliferating cell nuclear antigen (PCNA), MIB-1, MPM-2, HPV viral load, epidermal growth factor receptor, polyamines, and ploidy. The markers that have been demonstrated to be modulated in chemoprevention trials in the literature are quantitative histology and cytology, PCNA, MPM-2, HPV viral load, and polyamines. CONCLUSIONS: The surrogate endpoint biomarkers of most interest in future research should correlate well with HPV infection, be modulated by several therapeutic agents, and have limited variability and ease in measurement.

Antigens, Nuclear↗
PubMed2001

Reflectance spectroscopy for in vivo characterization of ovarian tissue.

BACKGROUND AND OBJECTIVE: To explore whether reflectance spectroscopy can differentiate normal ovary, benign neoplasms, and ovarian cancer. STUDY DESIGN/MATERIALS AND METHODS: Reflectance spectra (390-600 nm) were measured at three source-detector separations (SDS) in vivo at 64 sites in 16 patients undergoing oophorectomy. Parameters with largest statistical differences were identified. Based on these parameters algorithms were developed and evaluated. RESULTS: Promising parameters were the reflectance intensity from 540 to 580 nm (SDS, 1.1 mm), the slope of the reflectance spectrum from 490 to 520 nm (SDS, 1.1 mm), the slope from 510 to 530 nm (SDS, 2.1 mm), and the slope from 510 to 530 (SDS, 3 mm). Average sensitivity and specificity were 86 +/- 6% and 79 +/- 5% to separate normal ovary from benign neoplasms and cancers. Average sensitivity and specificity were 86 +/- 4% and 80 +/- 8% to separate ovarian cancers from benign neoplasms and normal ovary. CONCLUSION: Reflectance spectroscopy should be further investigated for ovarian cancer screening.

Algorithms↗
PubMed2001

Fluorescence spectroscopy of epithelial tissue throughout the dysplasia-carcinoma sequence in an animal model: spectroscopic changes precede morphologic changes.

BACKGROUND AND OBJECTIVE: The hamster cheek pouch carcinogenesis model, using chronic treatments of dimethylbenz[alpha]anthracene (DMBA) was used as a model system to investigate changes in epithelial tissue autofluorescence throughout the dysplasia-carcinoma sequence. STUDY DESIGN/MATERIALS AND METHODS: Fluorescence emission spectra were measured weekly from 42 DMBA-treated animals and 20 control animals at 337, 380, and 460 nm excitation. A subset of data in which histopathology was available was used to develop diagnostic algorithms to separate neoplastic and non-neoplastic tissue. The change in fluorescence intensity over time was examined in all samples at excitation-emission wavelength pairs identified as diagnostically useful. RESULTS: Algorithms based on autofluorescence can separate neoplastic and non-neoplastic tissue with 95% sensitivity and 93% specificity. Greatest contributions to diagnostic algorithms are obtained at 380 nm excitation, and 430, 470, and 600 nm emission. Changes in fluorescence intensity are apparent as early as 3 weeks after initial treatment with DMBA, whereas morphologic changes associated with dysplasia occur on average at 7.5-12.5 weeks after initial treatment. CONCLUSIONS: Fluorescence spectroscopy provides a potential tool to identify biochemical changes associated with dysplasia and hyperplasia, which precede morphologic changes observed in histologically stained sections.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2001

Fluorescence spectroscopy for in vivo characterization of ovarian tissue.

BACKGROUND AND OBJECTIVE: The objective of this study was to explore whether fluorescence spectroscopy signatures differed between normal variations within the ovary, benign neoplasms, and ovarian cancer. STUDY DESIGN/MATERIALS AND METHODS: Ovarian tissue fluorescence emission spectra were collected sequentially at 18 excitation wavelengths ranging from 330 to 500 nm from 11 patients undergoing oophorectomy and assembled into fluorescence excitation emission matrices (EEMs); biopsies corresponded to the area interrogated. Spectral areas that could differentiate normal ovary, benign neoplasms, and cancers were evaluated, using histopathology as the reference standard. RESULTS: The most promising measurements are (1) the integrated fluorescence intensity from 400 to 430 nm excitation at 460 nm emission, and (2) the ratios of fluorescence intensities at 330 nm excitation, 385 and 500 nm emission, and at 375 and 415 nm excitation, 460 nm emission. Simple systems to visualize these optical signatures at laparoscopy could be designed. CONCLUSION: Fluorescence spectroscopy may have the ability to distinguish ovarian cancers from normal ovarian structures and benign neoplasms, as well as differentiate between normal variations and metaplastic structures and should be further explored as a device for the early detection of ovarian cancers.

Female↗
PubMed2001

The management of ASCUS cervical cytologic abnormalities and HPV testing: a cautionary note.

A recently published study of the management of low-grade cytologic smears compared immediate colposcopy to human papillomavirus (HPV) triage and entry cytology smears (conservative management) as three triage techniques for managing atypical squamous cells of undetermined significance (ASCUS) smears (Atypical Squamous Cells of Undetermined Significance/Low-grade Squamous Intraepithelial Lesion Triage Study [ALTS]). The study reported a high sensitivity (96.3%) for HPV testing using hybrid capture 2 to detect cervical intraepithelial neoplasia (CIN) III. The authors concluded that HPV testing is a viable option for managing ASCUS smears. We have reviewed the published data from the ALTS trial and have found a large excess of colposcopies and biopsies in the HPV arm in comparison with the conservative management (cytology) arm. In addition, the ALTS trial quality control and pathology review results raise doubts about the diagnostic validity of the study to establish standards of clinical practice. Furthermore, until the 2-year follow-up analysis of the conservative management arm is completed to detect CIN III, a valid comparison between HPV triage and conservative management is not possible. We conclude that, based on published data, HPV testing for routine clinical management of low-grade cytologic abnormalities (ASCUS smears) is not warranted, and that HPV testing is currently an investigational tool.

Colposcopy↗
PubMed2001

Understanding the contributions of NADH and collagen to cervical tissue fluorescence spectra: modeling, measurements, and implications.

OBJECTIVE: At 380 nm excitation, cervical tissue fluorescence spectra demonstrate characteristic changes with both patient age and the presence of dysplasia. A Monte Carlo model was developed in order to quantitatively examine how intrinsic NADH and collagen fluorescence, in combination with tissue scattering and absorption properties, yield measured tissue spectra. METHODS: Excitation-emission matrices were measured for live cervical cells and collagen gel phantoms. Fluorescence microscopy of fresh tissue sections was performed to obtain the location and density of fluorophores as a function of patient age and the presence of dysplasia. A Monte Carlo model was developed which incorporated measurements of fluorophore line shapes and spatial distributions. RESULTS: Modeled spectra were consistent with clinical measurements and indicate that an increase in NADH fluorescence and decrease in collagen fluorescence create clinically observed differences between normal and dysplastic tissue spectra. Model predictions were most sensitive to patient age and epithelial thickness. CONCLUSIONS: Monte Carlo techniques provide an important means to investigate the combined contributions of multiple fluorophores to measured emission spectra. The approach will prove increasingly valuable as a more sophisticated understanding of in vivo optical properties is developed.

Adult↗
PubMed2001

Autofluorescence microscopy of fresh cervical-tissue sections reveals alterations in tissue biochemistry with dysplasia.

Fluorescence spectroscopy offers an effective, noninvasive approach to the detection of precancers in multiple organ sites. Clinical studies have demonstrated that fluorescence spectroscopy can provide highly sensitive, specific and cost-effective diagnosis of cervical precancers. However, the underlying biochemical mechanisms responsible for differences in the fluorescence spectra of normal and dysplastic tissue are not fully understood. We designed a study to assess the differences in autofluorescence of normal and dysplastic cervical tissue. Transverse, fresh tissue sections were prepared from colposcopically normal and abnormal biopsies in a 34-patient study. Autofluorescence images were acquired at 380 and 460 nm excitation. Results showed statistically significant increases in epithelial fluorescence intensity (arbitrary units) at 380 nm excitation in dysplastic tissue (106 +/- 39) relative to normal tissue (85 +/- 30). The fluorophore responsible for this increase is possibly reduced nicotinamide adenine dinucleotide. Stromal fluorescence intensities in the dysplastic samples decreased at both 380 nm (102 +/- 34 [dysplasia] vs 151 +/- 44 [normal]) and 460 nm excitation (93 +/- 35 [dysplasia] vs 137 +/- 49 [normal]), wavelengths at which collagen is excited. Decreased redox ratio (17-40% reduction) in dysplastic tissue sections, indicative of increased metabolic activity, was observed in one-third of the paired samples. These results provide valuable insight into the biological basis of the differences in fluorescence of normal and precancerous cervical tissue.

Adult↗
PubMed2001

Quantitative nuclear morphometry by image analysis for prediction of recurrence of ductal carcinoma in situ of the breast.

Clinical management of ductal carcinoma in situ (DCIS) remains a challenge because significant proportions of patients experience recurrence after conservative surgical treatment. Unfortunately, it is difficult to prospectively identify, using objective criteria, patients who are at high risk of recurrence and might benefit from additional treatment. We conducted a multi-institutional, collaborative case-control study to identify nuclear morphometric features that would be useful for identifying women with DCIS at the highest risk of recurrence. Tissue sections of archival breast tissue of 29 women with recurrent and 73 matched women with nonrecurrent DCIS were stained for DNA, and nuclei in the DCIS lesions were evaluated by image analysis. A clear correlation between mean fractal2_area (FA2) and nuclear grade was observed (P < 0.001), allowing an objective determination of nuclear grade. Several nuclear morphometric features, including mean and variance of variation of radius, mean area, mean and variance of frequency of high boundary harmonics (FQH), and variance in sphericity, were found to be useful in discriminating recurrent from nonrecurrent DCIS subjects. However, the nuclear features associated with recurrence differed between high- and low-grade lesions. For lesions with high FA2 (nuclear grade 3), mean variation of radius, mean FQH, and mean area alone yielded recurrence odds ratios of 4.55 [95% confidence interval (CI) 0.45-45.96], 3.86 (95% CI, 0.88-16.98), 2.90 (95% CI, 0.31-27.2), respectively. Using a summed feature model, high-FA2 lesions showing three poor prognostic features had an odds ratio of 15.63 (95% CI, 1.22-200), compared with those with zero or one poor prognostic feature. Lesions with low mean FA2 (nuclear grade 1 or 2) showing high variances in sphericity and FQH had an odds ratio of 7.71 (95% CI, 1.77-33.60). Addition of other features did not enhance the odds ratio or its significance. These results suggest that nuclear image analysis of DCIS lesions may provide an adjunctive tool to conventional pathological analysis, both for the objective assessment of nuclear grade and for the identification of features that predict patient outcome.

Adult↗
PubMed2001

Biomarker modulation in a nonhuman rhesus primate model for ovarian cancer chemoprevention.

OBJECTIVE: The objective of this study was to explore whether a nonhuman primate model could be developed to test drugs for the prevention of ovarian cancer. METHODS: Nineteen adult female Rhesus macaques were given fenretinide (4HPR), oral contraceptives (OCP), the combination (4HPR + OCP), or no medication for 3 months. Exploratory laparotomy was done pre- and postdrug to assess intermediary biomarkers of neoplastic phenotype, proliferation, response pathways, and growth-regulatory and metabolic markers. Fluorescence emission spectra were plotted for each group pre- and postdrug and means were overlaid on these plots and normalized. Fluorescence intensities were compared using the 2-tailed Student t test, (P = 0.1-0.01). RESULTS: All monkeys tolerated drugs and surgeries without difficulty. Histochemical markers showed no significant trend. However, fluorescence spectroscopy showed increased intensity at 450 nm excitation, 550 nm emission correlating with increased FAD presence. The 4HPR group (P = 0.01) showed higher intensity than the OCP group (P = 0.05-0.07) when compared with the controls. Decreased emission was seen at 350 nm excitation, 450 nm emission correlating with decreased NAD(P)H presence. The OCP group showed the largest change (P < 0.01), and the control group showed the smallest change. CONCLUSIONS: The nonhuman primate is an excellent model to test drug effect on the ovarian surface epithelium and merits additional study. Fluorescence spectroscopy was the most sensitive marker for drug activity and the apparent increase in NAD and FAD in the 4HPR group is consistent with the effect of 4HPR observed in cell culture. The differences between the OCP and the 4HPR groups suggest a different mechanism of activity of these drugs.

Animals↗
PubMed2001

A randomized clinical trial of 4-hydroxyphenylretinamide for high-grade squamous intraepithelial lesions of the cervix.

PURPOSE: Previous trials of topical trans-retinoic acid treatment of cervical intraepithelial neoplasia (CIN) grades 2 and 3 led to a statistically significant regression of CIN 2, but not CIN 3. We tested N-(4-hydroxyphenyl)retinamide (4-HPR), a promising oral retinoid that has been shown to induce apoptosis through nonretinoic receptor acid-mediated pathways, for its toxicity and efficacy against CIN 2/3. EXPERIMENTAL DESIGN: In a blinded randomized trial, 4-HPR at 200 mg/day for 6 months (with a 3-day/month drug holiday) was compared with placebo in patients with biopsy-proven CIN-2/3 [high-grade squamous intraepithelial lesions (HGSILs)]. Patients were treated with placebo or 4-HPR for 6 months, biopsied, and then followed for an additional 6 months. At the 12-month end point, they underwent either loop excision if a histological lesion was present or a biopsy from the original area of the lesion if no lesion was present. RESULTS: An interim analysis of blinded data showed a significantly worse prognosis at 12 months for one group. When the code was broken because of the poorer outcomes, we discovered that the 4-HPR treatment arm was performing more poorly than was the placebo at 6 and 12 months (25 versus 44% response rates at 6 months; 14 versus 50% at 12 months). Toxicity was not significant in either arm. CONCLUSIONS: 4-HPR at 200 mg/day with a 3-day/month drug holiday is not active compared with placebo in the treatment of HGSIL. Because 4-HPR is active in the laboratory, the lack of effect in our trial may indicate that higher doses are needed in patients to achieve comparable results.

Adult↗
PubMed2001

Rhesus macaque model for ovarian cancer chemoprevention.

PURPOSE: The objective of the study reported here was to explore whether a nonhuman primate model could be developed for chemoprevention of ovarian cancer. METHODS: An initial feasibility trial was done with three monkeys to determine tolerance for these drugs and for acquisition of surgical ovarian biopsy specimens. In the study, 19 female adult Macacca mulatta (rhesus macaques) were given fenretinide (4HPR) oral contraceptive (OCP), the combination of 4HPR+OCP, or no medication for three months. Laparotomy was performed before and after drug administration, and ovarian biopsy specimens were obtained to evaluate the potential for this animal as a model for ovarian cancer chemoprevention, as well as evaluating fluorescence spectroscopy and other potential biomarkers for ovarian cancer prevention studies. RESULTS: The monkeys tolerated the drugs, surgeries, and acquisition of multiple ovarian biopsy specimens with resultant minimal morbidity. On initial data analysis, fluorescence spectroscopy was the marker that appeared the most promising. CONCLUSIONS: On the basis of results of this study, this model merits further investigation. The rhesus monkey is an excellent candidate for a nonhuman primate model for ovarian cancer chemoprevention.

Animals↗
PubMed2000

Survey of female gynecologic oncologists and fellows: balancing professional and personal life.

OBJECTIVE: The aim of this study was to determine how female gynecologic oncologists have dealt with the challenge of combining childbearing and a career in gynecologic oncology and to identify other issues which need to be addressed to improve job satisfaction. METHODS: This survey of female members of the Society of Gynecologic Oncologists and fellows addressed demographics, timing of childbearing, type and cost of childcare, satisfaction with childcare choices, and mentorship. Those without children were queried about plans and reservations. Open-ended questions investigated how female gynecologic oncologists felt job satisfaction could be improved. RESULTS: A total of 65/110 (59%) attendings and 18/36 (50%) fellows responded. Three-fourths of respondents felt that the ideal time to have children was postfellowship. Timing of childbearing caused moderate to severe stress in the personal relationships of 23% of respondents. Median maternity leave was 6 weeks (1-120 days). Seventy-eight percent of female gynecologic oncologists with children employed a nanny. Over half of the respondents estimated weekly childcare cost at over $400. A successful balance between family and full-time practice was the most commonly cited quality of an ideal mentor. Sixty-six percent of the respondents replied to open-ended questions with narrative answers, revealing three major areas for improvement: childcare issues, increased flexibility in hours and duties (clinical, surgical, and research), and the need for more female mentoring. CONCLUSIONS: This survey highlighted the concerns of female gynecologic oncologists about achieving a successful balance between family and professional duties. It also revealed the ways in which women have responded and identified other issues that may be targeted to improve job satisfaction.

Data Collection↗
PubMed2000

Outcome and reproductive function after conservative surgery for borderline ovarian tumors.

OBJECTIVE: To study reproductive function and disease outcome in women with borderline ovarian tumors who were treated with conservative surgery. METHODS: Patients with borderline ovarian tumors were identified from institutional databases. Patients were eligible if they had pathologically confirmed borderline ovarian tumors, no prior sterilization, no history of radiation therapy, retained their uterus and ovarian tissue, and were younger than age 45. Information was acquired by retrospective medical record review and patient interview. RESULTS: Forty-three patients met the eligibility criteria. The median age was 25 years, with a range of 15-39 years. Twenty-six patients had serous tumors, and 17 had mucinous tumors. Fifteen had stage I disease, three had stage III, and 25 were unstaged. Follow-up was available for all patients (median, 5.7 years). Twenty-nine remained disease-free, and 14 developed a new primary lesion/recurrence, with a median time to recurrence of 39.3 months. Recurrence was more frequent in patients treated with ovarian cystectomy than in those treated with oophorectomy alone (58% compared with 23%) (P <.04). After treatment, 29 of 36 patients (81%) retained normal menstrual cycles, and 12 of 24 patients attempting pregnancy conceived 25 pregnancies. Most patients were highly satisfied with conservative surgery. CONCLUSION: Conservative surgery remains a therapeutic option in selected patients with borderline ovarian tumors. Although the rate of new lesion/recurrence is relatively high, especially in those treated with ovarian cystectomy, mortality from cancer remains low. Many patients who desire pregnancy are able to conceive and deliver healthy offspring after conservative surgery.

Adolescent↗