Clitoral neuroma after female genital mutilation/cutting: a rare but possible event.

INTRODUCTION: Female genital mutilation/cutting (FGM/C), in particular, type III, also called infibulation, can cause various long-term complications. However, posttraumatic neuroma of the clitoris is extremely rare; only one case was previously reported in the literature. AIM: The aim of this study was to describe the case of a patient presenting a clitoral neuroma post-FGM/C in detail and her successful multidisciplinary treatment. METHODS: We report the case of a 24-year-old woman originating from Somalia presenting a type III a-b FGM/C who attended our outpatient clinic at the Geneva University Hospitals complaining of primary dysmenorrhea and a post-mutilation painful clitoral mass. The mass was clinically diagnosed as a cyst and surgically removed. Histopathological analysis revealed that it was a posttraumatic neuroma and a foreign body granuloma around the ancient surgical thread. Our patient was also offered a multidisciplinary counseling by a specialized gynecologist on FGM/C, a sexologist, and a reproductive and sexual health counselor. RESULTS: One month after surgical treatment, the vulvar pain was over. CONCLUSIONS: This is the second case of clitoral neuroma after FGM/C reported and the first with complete clinical, as well as histopathological documentation and multidisciplinary care. Considering the high frequency of clitoral cysts in case of infibulation, clitoral neuroma should be considered in the differential diagnosis. In this case, if symptomatic, the treatment should be surgery, clinical follow-up, and counseling. If necessary, appropriate sexual therapy should be offered too.

[Sexual assaults in Geneva between 2006 and 2010]. / Sexuelle Ubergriffe in Genf (2006 bis 2010).

In Geneva, all sexual assault victims are examined both by a gynaecologist and a forensic pathologist with special training in clinical forensic medicine. Between 2006 and 2010, 473 victims were examined following such an assault. Over the years, the number of sexual assaults rose steadily. Most victims were aged between 15 and 30 years. The majority of the assaults occurred at night and on the weekend and often happened at the place where the perpetrator or the victim lived. Usually, the offender acted alone and was known to the victim. Many victims hesitate to present for an examination, which makes it difficult to collect evidence. Penetration was usually vaginal and without the use of a condom. Injuries on the body or genitals were seen in only half of the cases for the first ones and in less than one third for the second ones. Quite often (at least in 42 % of the cases), the victim consumed alcohol before the assault and the use of drugs--especially cannabis--was not uncommon either.

Accuracy of optical spectroscopy for the detection of cervical intraepithelial neoplasia: Testing a device as an adjunct to colposcopy.

Testing emerging technologies involves the evaluation of biologic plausibility, technical efficacy, clinical effectiveness, patient satisfaction, and cost-effectiveness. The objective of this study was to select an effective classification algorithm for optical spectroscopy as an adjunct to colposcopy and obtain preliminary estimates of its accuracy for the detection of CIN 2 or worse. We recruited 1,000 patients from screening and prevention clinics and 850 patients from colposcopy clinics at two comprehensive cancer centers and a community hospital. Optical spectroscopy was performed, and 4,864 biopsies were obtained from the sites measured, including abnormal and normal colposcopic areas. The gold standard was the histologic report of biopsies, read 2 to 3 times by histopathologists blinded to the cytologic, histopathologic, and spectroscopic results. We calculated sensitivities, specificities, receiver operating characteristic (ROC) curves, and areas under the ROC curves. We identified a cutpoint for an algorithm based on optical spectroscopy that yielded an estimated sensitivity of 1.00 [95% confidence interval (CI) = 0.92-1.00] and an estimated specificity of 0.71 [95% CI = 0.62-0.79] in a combined screening and diagnostic population. The positive and negative predictive values were 0.58 and 1.00, respectively. The area under the ROC curve was 0.85 (95% CI = 0.81-0.89). The per-patient and per-site performance were similar in the diagnostic and poorer in the screening settings. Like colposcopy, the device performs best in a diagnostic population. Alternative statistical approaches demonstrate that the analysis is robust and that spectroscopy works as well as or slightly better than colposcopy for the detection of CIN 2 to cancer.

Comparison of women's breast cancer risk factors in Geneva, Switzerland and Shanghai, China.

BACKGROUND: We compared the prevalence of known and suspected breast cancer risk factors among women in Geneva, Switzerland, where the annual incidence of breast cancer is high, to women in Shanghai, China, where incidence is lower. METHODS: Different translations of the same woman's health questionnaire were administered to women aged 35 to 74 years in Shanghai (n=631) and Geneva (n=1,212) during 1996-1997 and reproductive and lifestyle factors compared. RESULTS: Shanghai women reported older age at menarche (median 15 vs. 13 years), fewer nulliparity (7.3 vs. 21.6%), younger age at first live birth (median 25.7 vs. 28.4 years), and shorter duration of reproductive life (median 35.7 vs. 38.4 years). Geneva women had a greater prevalence of current cigarette smoking (22.4 vs. 1.8%), oral contraceptive use (61.1 vs. 10.0%), hormone replacement therapy use (23.4 vs. 0.8%), and family history of breast cancer (8.6 vs. 1.4%). Among women who breastfed, Shanghai women had more than twice the duration of breastfeeding than Geneva women (median 48 vs. 21 weeks). CONCLUSIONS: Differences in the prevalence of breast cancer risk factors, in particular reproductive characteristics, may contribute to the large contrast in cumulative risk between women living in Geneva and Shanghai.

Prognostic value of histopathology and trends in cervical cancer: a SEER population study.

BACKGROUND: Histopathology is a cornerstone in the diagnosis of cervical cancer but the prognostic value is controversial. METHODS: Women under active follow-up for histologically confirmed primary invasive cervical cancer were selected from the United States Surveillance, Epidemiology, and End Results (SEER) 9-registries public use data 1973-2002. Only histologies with at least 100 cases were retained. Registry area, age, marital status, race, year of diagnosis, tumor histology, grade, stage, tumor size, number of positive nodes, number of examined nodes, odds of nodal involvement, extent of surgery, and radiotherapy were evaluated in Cox models by stepwise selection using the Akaike Information Criteria. RESULTS: There were 30,989 records evaluable. From 1973 to 2002, number of cases dropped from 1,100 new cases/year to 900/year, but adenocarcinomas and adenosquamous carcinoma increased from 100/year to 235/year. Median age was 48 years. Statistically significant variables for both overall and cause-specific mortality were: age, year of diagnosis, race, stage, histology, grade, hysterectomy, radiotherapy, tumor size and nodal ratio. The histological types were jointly significant, P < 0.001. Cause-specific mortality hazard ratios by histological type relatively to non-microinvasive squamous cell carcinoma were: microinvasive squamous cell carcinoma 0.28 (95% confidence interval: 0.20-0.39), carcinoma not otherwise specified 0.91 (0.79-1.04), non-mucinous adenocarcinoma 1.06 (0.98-1.15), adenosquamous carcinoma 1.35 (1.20-1.51), mucinous adenocarcinoma 1.52 (1.23-1.88), small cell carcinoma 1.94 (1.58-2.39). CONCLUSION: Small cell carcinoma and adenocarcinomas were associated with poorer survival. The incidental observation of increasing numbers of adenocarcinomas despite a general decline suggests the inefficiency of conventional screening for these tumors. Increased incidence of adenocarcinomas, their adverse prognosis, and the young age at diagnosis indicate the need to identify women who are at risk.

Results of a phase II double-blinded randomized clinical trial of difluoromethylornithine for cervical intraepithelial neoplasia grades 2 to 3.

PURPOSE: Our purpose was to conduct a double-blinded randomized trial of difluoromethylornithine (DFMO) at 0.125, 0.5 gm/m2, versus placebo in the treatment of cervical intraepithelial neoplasia (CIN) grades 2 to 3. A promising phase I study has shown histopathologic responses at these dose levels. EXPERIMENTAL DESIGN: Patients with histopathologically confirmed CIN 2-3 lesions were recruited from a colposcopy clinic and underwent Papanicolaou testing, human papillomavirus testing, and colpophotography. They took oral contraception and DFMO or placebo elixir for 28 days and filled out the National Cancer Institute common toxicity calendars. They returned for follow-up and a repeat Papanicolaou smear, colpophotograph, and loop excision of the cervix. RESULTS: There were no statistically significant differences among the arms in histopathologic response. This could no be explained by any biases in risk factors. The prominent toxicities were diarrhea, dizziness, nausea, and headaches. There were no differences in the toxicities among arms. The Papanicolaou smear was a poor biomarker of response and correlated poorly with the histopathology. CONCLUSIONS: DFMO is no active at 0.125 and 0.5 gm/m2 for 28 days when given orally in CIN 2-3. Higher oral doses or longer administration is necessary, supporting data from breast trials. Alternatively, a trial of topical DFMO might merit attention as activity has been noted in trials of actinic keratoses.

Biomarkers and their use in cervical cancer chemoprevention.

Cervical cancer chemoprevention agents under study include diet and micronutrients (particularly beta-carotene, folate, and vitamins A, C, and E); medications such as retinoids (retinyl acetate gel, all-trans-retinoic acid, and 4-hydroxyphenylretinamide) that are chemically related to micronutrients; and other chemopreventives meant to affect the carcinogenic process at the cellular level, including such polyamine synthesis inhibitors as alpha-difluoromethylornithine. Agents become reasonable candidates for study when they have a biologic rationale, they are of low toxicity, and they can be taken for a long period of time. Since the human papillomavirus (HPV) is the major etiologic agent, the medication should show activity against HPV-positive preinvasive and invasive cell lines. The medication needs to be of low toxicity because it may be taken for long periods of time and less toxicity is tolerated in the precancerous setting. Until 1995, none of the studies used surrogate end point biomarkers (SEBs), relying instead on histologic and colposcopic regression as end points. All studies typically included subjects with cervical intraepithelial neoplasia. Conclusions to be drawn from these studies include the following: Though micronutrients are logical candidates for chemoprevention, they haven't worked consistently, and the reasons remain unclear. Furthermore, SEBs need to be validated in phase I trials. Finally, a better understanding of the role of HPV needs elucidation, including an understanding of the relationship of the medication to HPV status and of the immunobiology of HPV throughout the trial.

Lymphangioma circumscriptum of the vulva: a review of the literature.

OBJECTIVE: To promote proper identification and management of this rare entity by presenting a review of the literature, a case report, and illustrations of its presentation and pathology. DATA SOURCES: Sources searched included the literature contained in the National Library of Medicine's PubMed database, using the term "lymphangioma circumscriptum" combined with "vulva." Other search terms used were "capillary lymphangioma," "lymphangiectasia," and "dermal lymphangioma." Sources also included articles predating the PubMed database that were cited by other writers. METHODS OF STUDY SELECTION: Selections were restricted to the English-language medical literature published since 1960, and the search resulted in retrieval of 3272 published papers about lymphangioma. TABULATION, INTEGRATION, AND RESULTS: Congenital lymphangioma circumscriptum of the vulva has been reported in 11 patients, including one case reported and illustrated in this paper, and acquired lymphangioma circumscriptum has been reported in 20. It affects females 9-76 years old (mean 42.5 years). Clinically, it is characterized by persistent clusters of thin-walled vesicles filled with clear fluid. The diagnosis is usually made by biopsy, as these lesions often mimic such infectious diseases as molluscum contagiosum. Management options have included surgical excision of the skin and subcutaneous tissue, surface abrasion by laser or sclerosing therapy, and observation. CONCLUSION: From this comprehensive review, which includes the clinicopathologic features of both the congenital and acquired forms, illustrations from the rarest form, and a summary of treatment approaches, we conclude that lymphangioma circumscriptum poses a diagnostic challenge the risks of which are misdiagnosis and mistreatment. These risks would likely be reduced were a database of cases accessible that permitted long-term follow-up and better assessment of presenting characteristics and treatment options.

[Optical diagnosis of cervical dysplasia]. / Diagnostic optique des lésions dysplasiques du col utérin.

Cervix cancer is a curable disease when diagnosed at an early stage. Screening of cervical lesions by cytology and colposcopy with in situ staining has allowed for substantial progress in early diagnosis and consequently the cure of cervix cancer. Nevertheless, because of its low specificity, this approach generally implies repetitive tissue sampling and, thus a relative long time before the treatment of the lesions. Furthermore, the cost of preparation and analysis of biopsy samples is sufficiently high to represent a burden for industrialized countries and a virtual impossibility for the developing world. To overcome these problems, various biophotonic methods using optical fibers have been developed to allow for detection of cervical epithelial anomalies in a specific, fast and non-invasive way. This process, known as "optical biopsy", is based on the measurement of light-tissue interactions, which are analysed by various mathematical and data processing methods, to provide information on the metabolism and morphology of epithelial tissue. Currently investigated methods can be distinguished according to the type of signal used to probe the tissue (fluorescence, reflectance), the depth of analysed tissue (surface analysis, confocal imaging, tomography), the analysis modalities (spectral measurements or imaging), and the use of additive molecules (contrasting or photosensitizing agents, inorganic fluorophores). While most of the methods remain experimental, constant progress in the understanding of the mechanisms of light behavior in biological environments as well as advances in optical fibers technology, will make a number of these methods soon available for clinical practice to contribute efficiently to the reduction of biopsy number and cost of cervical screening.

Primary breast lymphomas.

The diagnosis, prognostic factors, and optimal management of primary breast lymphomas (PBL) is difficult. Seven patients recorded at the Geneva Cancer Registry between 1973-1998 were reviewed. Five patient had diffuse large B-cell lymphoma, one a follicular lymphoma and one a MALT-lymphoma. All patients had clinical and radiological findings consistent with breast cancer and underwent mastectomy, which is not indicated in PBL. Diagnosis should be established prior to operative interventions, as fine needle aspiration missed the diagnosis for one patient and intra-operative frozen sections for 3 patients in our study. Five-year and 10-year overall survivals were 57% and 15%, respectively. Of the 3 patients who died from PBL, 2 had tumors that were Bcl-2 positive but Bcl-6 negative. All 3 surviving patients have positive Bcl-2 and Bcl-6 immunostaining, which could be important prognostic factors if confirmed by a larger study.

Diagnosis of vulvar lesions by non-invasive optical analysis: a pilot study.

A procedure that could allow an early in vivo and non-invasive detection of vulvar lesions would be extremely useful. We tested an innovative optical method (Optiprobe), which uses a harmless, visible light source for the in vivo, on-line detection of minimal alterations in the structure of vulvar epithelium. A group of 3 female volunteers without gynecological symptoms were first screened to evaluate optical properties of normal vulvar tissue. Next, a group of 16 patients undergoing gynecological examination for vulvar lesions was evaluated by the Optiprobe at suspected sites before these sites were biopsied for histological analysis. Adjacent, non-involved sites were also measured to provide internal controls. Histological analysis of the biopsies identified one case that did not show obvious alterations, 4 cases of high-grade vulvar intraepithelial neoplasia (VIN), 5 cases of vulvitis, and 6 cases of lichen sclerosis (LS).The optical properties of the VIN cases were significantly different from those of controls, due to a decrease in the absorption spectra and an increase in the scattering spectra. In contrast, a significant increase in the absorption spectra and a decrease in the scattering spectra were observed in the cases of vulvitis. In the LS cases, the absorption spectra were as in controls, whereas the scattering spectra were significantly decreased. We conclude that the Optiprobe provides a useful tool for a rapid and non-invasive detection of vulvar alterations. The method should contribute to reduce the number of biopsies and to facilitate the long-term follow-up of vulvar lesions.

Older female cancer patients: importance, causes, and consequences of undertreatment.

Despite increased interest in treatment of senior cancer patients, older patients are much too often undertreated. This review aims to present data on treatment practices of older women with breast and gynecologic cancers and on the consequences of undertreatment on patient outcome. We also discuss the reasons and validity of suboptimal care in older patients. Numerous studies have reported suboptimal treatment in older breast and gynecologic cancer patients. Undertreatment displays multiple aspects: from lowered doses of adjuvant chemotherapy to total therapeutic abstention. Undertreatment also concerns palliative care, treatment of pain, and reconstruction. Only few studies have evaluated the consequences of nonstandard approaches on cancer-specific mortality, taking into account other prognostic factors and comorbidities. These studies clearly showed that undertreatment increased disease-specific mortality for breast and ovarian cancers. For other gynecological cancers, data were insufficient to draw conclusions. Objective reasons at the origin of undertreatment were, notably, higher prevalence of comorbidity, lowered life expectancy, absence of data on treatment efficacy in clinical trials, and increased adverse effects of treatment. More subjective reasons were putative lowered benefits of treatment, less aggressive cancers, social marginalization, and physician's beliefs. Undertreatment in older cancer patients is a well-documented phenomenon responsible for preventable cancer deaths. Treatments are still influenced by unclear standards and have to be adapted to the older patient's general health status, but should also offer the best chance of cure.

Moving toward individualized therapy based on NER polymorphisms that predict platinum sensitivity in ovarian cancer patients.

OBJECTIVE: Platinum-based chemotherapy exerts its cytotoxic effect by forming DNA adducts and subsequently inhibiting DNA replication. Removing platinum DNA adducts requires the nucleotide excision repair (NER) pathway. The xeroderma pigmentosum (XP) complementation group of genes plays an essential role in the NER pathway. We hypothesized that genetic polymorphisms in XP genes may predict clinical response to platinum chemotherapeutic treatment and survival in women with gynecological cancers. METHOD: We genotyped 146 cases of advanced epithelial ovarian cancer for XP gene polymorphisms using the PCR-RFLP method. Kaplan-Meier plots and the log-rank test were used to assess associations between survival and recurrence-free interval and the XP gene polymorphisms. Hazard ratio of response was estimated from an adjusted multivariate Cox proportional hazard model. RESULTS: Women with a heterozygous variant XPA allele had shorter median survival (21.5 months, P=0.03) and shorter median time to recurrence (11.3 months, P=0.05) than women with the homozygous wild-type allele (37.9 and 13.9 months, respectively). Women with a homozygous variant XPG allele had significantly shorter median survival (8.3 months, P=0.006) compared with women with the homozygous XPG wild-type allele (24.6 months). Polymorphisms in XPC, XPD exon10, and XPD exon23 were associated with a decreased risk of recurrence and death, but were not statistically significant. CONCLUSIONS: This study suggests that NER gene polymorphisms may correlate with recurrence and patient survival. A larger sample size is needed to assess platinum chemotherapy response with these polymorphisms. These findings may help identify subgroups of cancer patients likely to benefit from individualized treatment strategies. Our next study will examine NER gene polymorphisms in cervical cancer patients.

Aberrant expression of BARD1 in breast and ovarian cancers with poor prognosis.

Mutations in tumor-suppressor gene BARD1 have been found in inherited and spontaneous breast, ovarian and uterine cancers. BARD1 plays a critical role in DNA repair and ubiquitination as binding partner of BRCA1, with which it colocalizes to nuclear dots. Independently of BRCA1, BARD1 can induce p53-dependent apoptosis in response to genotoxic stress. Therefore, BARD1 or p53 might be defective in cancer cells spared from apoptosis. We investigated BARD1 and p53 expression in ovarian, breast and non-small-cell lung cancers. BARD1 expression was highly upregulated and cytoplasmic in most cancer cells, while weak nuclear staining was observed in the surrounding normal tissue. Maximal BARD1 expression was associated with the most malignant ovarian cancer, clear cell carcinoma. In breast cancer, BARD1 expression was correlated with poor differentiation and large tumor size, established factors of poor prognosis, as well as short disease-free survival. In contrast to breast and ovarian cancers, no correlation of BARD1 expression with either grade or stage could be determined for lung cancer. RT-PCR, performed on 10 ovarian cancers, revealed absence of the 5' portion of the BARD1 transcript in 7 tumors, and sequencing of the remaining 3 identified a missense mutation (A1291G) resulting in an amino acid change of glutamine 406 to arginine. These data suggest that genetic and epigenetic changes might lead to elevated cytoplasmic expression of BARD1 and that cytoplasmic BARD1 might be a poor prognostic factor for breast and ovarian cancers.

Cervical chromosome 9 polysomy: validation and use as a surrogate endpoint biomarker in a 4-HPR chemoprevention trial.

BACKGROUND: Several genetic alterations have been described in cervical cancers including: human papillomavirus (HPV) E6 and E7 oncoproteins, subtle sequence changes, alterations in chromosome number, chromosome translocations, and gene amplifications. This report focuses on establishing chromosome 9 polysomy as a cervical biomarker of chromosome instability and using it in a chemoprevention trial. Chromosomal instability is a feature of most human cancers and is probably an early event in the process. METHODS: We used 37 cervical cone specimens to validate chromosome 9 polysomy as a biomarker and then tested its modulation in a randomized clinical trial of 4-hydroxyphenylretinamide (4-HPR) in 39 patients with three blinded histopathologic reviews. No confounders were identified. In the present study, immunohistocytochemical analysis of Chromosome 9 polysomy was carried out and quantitatively measured. RESULTS: The Cell Index, the ratio of the number of total chromosome 9 copies to the total number of ells, increases significantly in archival samples as the cervix changes from normal to CIN to invasive cancer. In the chemoprevention trial, chromosome 9 polysomy was used as a biomarker and supported the histological analysis showing that 4-HPR impaired the natural regression response. CONCLUSIONS: Chromosome 9 polysomy appears to be a marker of genetic instability that can be used in chemoprevention trials as a surrogate endpoint biomarker. In this randomized trial of 4-HPR, the chromosome 9 polysomy measurements supported the clinical histopathologic reading in a quantitative manner suggesting that 4-HPR at 200 mg/day may have been inhibiting the regression seen in the placebo arm by inducing genetic instability.

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.

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.

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.