Search

Background: We examined the baseline prevalence of penile, scrotal, perineal/perianal, and intra-anal human papillomavirus (HPV) infection in human immunodeficiency virus (HIV)-seronegative men who have sex with men (MSM).Methods: Data were analyzed from 602 MSM aged 16-27 years with ≤ 5 lifetime sexual partners. Serum samples were tested for antibodies to HPV6/11/16/18. Swab samples were collected separately from several anogenital areas for detection of HPV6/11/16/18/31/33/35/39/45/51/52/56/58/59 DNA.Results: The prevalence of any tested HPV type was 18.5% at the penis, 17.1% at the scrotum, 33.0% at the perineal/perianal region, 42.4% in the anal canal, and 48.0% at any site. Overall, 415 MSM (69.7%) were negative to HPV 6, 11, 16, and 18 at enrollment by both serology and DNA detection. Men residing in Europe and Latin America had significantly increased risk of HPV infection at external genital sites and the anal canal compared to men from Australia. Tobacco use and greater number of lifetime sexual partners was associated with higher HPV infection prevalence.Conclusions: The prevalence of HPV infection is high among young sexually active MSM, with the anal canal being the most common site of infection. Lifetime number of sexual partners was the most important modifiable risk factor for anogenital HPV infection. [ABSTRACT FROM AUTHOR]

Background: We examined the baseline prevalence of penile, scrotal, and perineal/perianal human papillomavirus (HPV) in heterosexual men (HM). We also evaluated baseline characteristics of HM to assess factors associated with prevalent HPV detection.Methods: We tested serum samples from 3463 HM aged 16-24 years with 1-5 lifetime female sexual partners for antibodies to HPV 6, 11, 16, and 18. We collected baseline swab specimens for the detection of DNA of HPV 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59 from 3 areas: penile, scrotal, and perineal/perianal. Risk factors for prevalent HPV DNA detection were evaluated.Results: The prevalence of any tested HPV type was 18.7% at the penis, 13.1% at the scrotum, 7.9% at the perineal/perianal region, and 21.0% at any site. Having >3 lifetime female sexual partners had the greatest impact on HPV prevalence: odds ratio (OR) 3.2 (95% confidence interval (CI) 2.1-4.9) for HPV 6, 11, 16, and 18; and OR 4.5 (95% CI 3.3-6.1) for all HPV types tested. HPV DNA detection was highest in Africa. Neither condom usage nor circumcision was associated with HPV DNA prevalence.Conclusion: Genital-HPV DNA detection is common in young, sexually active HM. We found HPV to be most prevalent in African men and least prevalent in men from the Asia-Pacific region. Increased numbers of sexual partners was an important risk factor for HPV DNA prevalence. [ABSTRACT FROM AUTHOR]

Objective: To assess the contraceptive efficacy, safety, and tolerability of a contraceptive transdermal delivery system, (TDS; TWIRLA Ⓡ ) containing levonorgestrel (LNG) and ethinyl estradiol (EE)., Study Design: This single-arm, open-label, multicenter, 1-year (13 cycle), phase 3 study enrolled sexually active women ≥18 years old at risk for pregnancy irrespective of body mass index (BMI). Women used patches in 28-day cycles (3 consecutive administrations of 7-day patches followed by 7 days off-treatment/patch-free week). We assessed contraceptive efficacy by the Pearl Index (PI) in women 18 to 35 years, excluding cycles without intercourse or when other contraceptive methods were used., Results: The study enrolled 2032 demographically diverse women in the US, of which 35.3% had a BMI ≥30 kg/m 2 . In the primary efficacy analysis, the PI (95% confidence interval) was 5.8 (4.5-7.2) pregnancies per 100 woman-years. PIs trended higher as BMI increased; the PI was 4.3 (2.9-5.8) in women with BMI <30 kg/m 2 and 8.6 (5.8-11.5) in women with BMI ≥30 kg/m 2 . Hormone-related treatment-emergent adverse events included nausea (4.1%) and headache (3.6%); 11% of women discontinued due to adverse events. Four women (all with BMIs ≥30 kg/m 2 ) reported thromboembolic events considered related to treatment., Conclusions: The low-dose LNG/EE TDS was effective in preventing pregnancy in a population of women representative of US demographics. Efficacy was reduced in women with BMI ≥30 kg/m 2 . The TDS safety and tolerability profile was consistent with other similar dose combined hormonal contraceptives. Results of this phase 3 study supported the US Food and Drug Administration approval of TWIRLA Ⓡ for prevention of pregnancy in women with BMI <30 kg/m 2 ., Implications: TDS (120 µg/day levonorgestrel and 30 µg/day ethinyl estradiol) is an effective, low-dose transdermal contraceptive patch with favorable tolerability profile approved for prevention of pregnancy in women with BMI <30 kg/m 2 . TDS has reduced effectiveness in women with BMI ≥30 kg/m 2 ., (Copyright © 2020. Published by Elsevier Inc.)

Due to sporadic and not easily accessible cervical cancer screening, human papillomavirus (HPV)-related cervical cancer is a leading cause of cancer death in Sub-Saharan African women. This study was designed to assess the safety and immunogenicity of a quadrivalent human papillomavirus (qHPV) vaccine in sub-Saharan African women. This seven month, double-blind study enrolled 250 healthy, human immunodeficiency virus (HIV)-uninfected females ages 9-26 residing in Ghana, Kenya, and Senegal. Thirty females ages 13-15 and 120 females ages 16-26 received qHPV vaccine. In addition, 100 females ages 9-12 y were randomized in a 4:1 ratio to receive either qHPV vaccine (n = 80) or placebo (n = 20 ). The primary immunogenicity hypothesis was that an acceptable percentage of subjects who received the qHPV vaccine seroconvert to HPV6/11/16/18 at 4 weeks post-dose 3, defined as the lower bound of the corresponding 95% confidence interval (CI) exceeding 90%. The primary safety objective was to demonstrate that qHPV vaccine was generally well tolerated when administered in a 3-dose regimen. The pre-specified statistical criterion for the primary immunogenicity hypothesis was met: the lower bound of the 95% exact binomial CI on the seroconversion rate was at least 98% for each vaccine HPV type and all subjects seroconverted by 4 weeks post-dose 3. Across vaccination groups, the most common adverse events (AE) were at the injection site, including pain, swelling, and erythema. No subject discontinued study medication due to an AE and no serious AEs were reported. There were no deaths. This study demonstrated that qHPV vaccination of sub-Saharan African women was highly immunogenic and generally well tolerated.

Purpose: Human papillomavirus (HPV) is the causative agent of cervical cancer. Black women are disproportionally diagnosed and have higher mortality from cervical cancer in the United States. Here we describe the prophylactic efficacy and safety of a quadrivalent HPV-6/11/16/18 vaccine in black women., Methods: A total of 700 black women from Latin America, Europe, and North America (aged 16-24 years) received the vaccine or placebo in one of two studies. Analyses focused on the efficacy and safety of the vaccine., Results: Baseline rates of Chlamydia trachomatis infection and history of past pregnancy were more than twice as high in black women compared with the non-black women who were enrolled in these trials. HPV-6/11/16 or 18 DNA was detected in 18% of black women versus 14.6% in non-black women at day 1. For black women, vaccine efficacy against disease caused by HPV-6/11/16/18 was 100% for cervical intraepithelial neoplasia (0 vs. 15 cases; 95% confidence interval, 64.5%-100%) and 100% for vulvar and vaginal intraepithelial neoplasia and condylomata acuminata (0 vs. 17 cases; 95% confidence interval, 69.3%-100%). There were no serious vaccine-related adverse experiences. A similar proportion of pregnancies resulted in live births (75.8% vaccine; 72.7% placebo) and fetal loss (24.2% vaccine; 27.3% placebo)., Conclusions: Prophylactic quadrivalent HPV-6/11/16/18 vaccination of young black women demonstrated high efficacy, safety, and tolerability. HPV vaccination has the potential to reduce cervical cancer-related health disparities both in the United States and around the world., (Copyright © 2013 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Human papillomavirus (HPV) infection can lead to significant disease in males, including anogenital warts, intraepithelial neoplasias, and several types of oral and anogenital cancers. The quadrivalent HPV (type 6/11/16/18) L1 virus-like particle (VLP) vaccine (qHPV vaccine; Gardasil) has recently been demonstrated to prevent persistent infection and associated disease related to vaccine HPV types in males. We report the overall immunogenicity results from a trial of the quadrivalent HPV vaccine in males. Overall, 3,463 heterosexual men and 602 men who had sex with men were enrolled into a randomized, placebo-controlled, double-blind safety, immunogenicity, and efficacy study. Serum samples were collected prior to vaccination at day 1 and at months 7, 24, and 36 postvaccination. Immunogenicity was evaluated with a multiplex, competitive Luminex immunoassay. Almost all subjects (97.4 to 99.2%) seroconverted for vaccine HPV types by month 7. At month 36, 88.9%, 94.0%, 97.9%, and 57.0% of subjects were still seropositive for HPV-6, -11, -16, and -18, respectively. For all vaccine HPV types, black subjects had significantly higher antibody titers at month 7 than did both Caucasian and Asian subjects. An anamnestic antibody response was seen in men seropositive before vaccination. The vaccine was highly immunogenic in males 16 to 23 years of age; responses were comparable to those observed in women. Furthermore, the immune responses were consistent with the established efficacy of the vaccine in the prevention of incident and persistent HPV infection, anogenital warts, and anal intraepithelial neoplasia.

Background: Prophylactic vaccination with a quadrivalent HPV (types 6, 11, 16, 18) vaccine (qHPV) has been shown to prevent infection with HPV 6/11/16/18 and associated disease in women and more recently, in men. Here we report on the safety and reactogenicity of the qHPV vaccine in males. A total of 4,065 healthy males aged 16-26 years were enrolled into a randomized, placebo-controlled, double-blind trial. Subjects were randomized 1:1 to receive qHPV vaccine or placebo at day 1, month 2, and month 6. Safety and tolerability were assessed via the collection of reported adverse experiences (AEs). All serious AEs (vaccine- or procedure-related or not) and all deaths occurring during the study were recorded. Safety analyses were conducted in all subjects who received at least one dose of vaccine or placebo. The proportion of subjects who reported at least one injection-site AE was higher in the qHPV vaccine group versus the placebo group (60.1% vs 53.7%, respectively), however most of these AEs were mild/moderate in intensity. The incidence of at least one systemic AE was comparable between the vaccine and placebo groups (31.7% vs 31.4%, respectively). There were no vaccine-related serious AEs or deaths. The occurrence of AEs did not increase with each successive injection, and among trial participants who were seropositive for at least one vaccine HPV type at enrollment, the profile of adverse events was similar to that of the entire study cohort. The qHPV vaccine was generally well tolerated in males aged 16-26 years and had a favorable safety profile.

The primary objective of this report is to describe the detection of adenocarcinoma in situ (AIS) and associated human papillomavirus (HPV) type distribution that was observed in the context of two phase 3 clinical trials of a quadrivalent HPV6/11/16/18 vaccine. In this intention-to-treat analysis, we include all women who had at least one follow-up visit postenrollment. Healthy women (17,622) aged 15-26 with no history of HPV disease and a lifetime number of less than five sex partners (average follow-up of 3.6 years) were randomized (1:1) to receive vaccine or placebo at day 1, months 2, and 6. Women underwent colposcopy and biopsy according to a Papanicolaou triage algorithm. All tissue specimens were tested for 14 HPV types and were adjudicated by a pathology panel. During the trials, 22 women were diagnosed with AIS (six vaccine and 16 placebo). There were 25 AIS lesions in total, with HPV16/18 present in 96% (24 of 25 with 15 of 25 as single infections). Only two of 22 women had concomitant cytology results suggesting glandular abnormality. Colposcopic impressions (25 total) were either negative or indicated squamous lesions only. Of women with AIS, all six in the vaccine cohort and seven of 16 in the placebo cohort were infected at baseline with the same HPV type that was detected in the AIS lesion. Concurrent squamous lesions were detected in 20 of these 22 women. In summary, our findings show that AIS evades colposcopic and cervical cytologic detection. As most AIS lesions were HPV16/18-related, prophylactic HPV vaccination should reduce the incidence of invasive adenocarcinoma., (Copyright © 2011 UICC.)

Purpose: We have previously shown that CLDN4 (encoding claudin-4), a cell tight junction (TJ) protein, is highly expressed in human epithelial ovarian carcinomas (EOC) but undetectable in normal ovaries. CLDN4 has been identified as a specific receptor for C terminus of Clostridium perfringens enterotoxin (C-CPE), a nontoxic molecule that may disrupt TJ barrier function and enhance cellular absorption. The purpose of this study was to determine the potential clinical applications of C-CPE and its effects on CLDN4 expression in EOC., Experimental Design: Using a 3-dimensional culture model and monolayer culture of EOC cells, we examined the effects of C-CPE on CLDN4 expression by quantitative real-time PCR, immunofluorescence, and Western blot. The synergistic effect of C-CPE to clinically relevant chemotherapies (Taxol and Carboplatin) was observed in EOC culture and xenograft mice. Furthermore, we determined through oligonucleotide microarray analysis that the transcript profile alterations dysregulated as a consequence of C-CPE treatment., Results: C-CPE treatment decreased protein expression and relocated CLDN4 from cell-cell contact regions to the cytoplasm. Particularly, C-CPE sensitized EOC cells to chemotherapeutic administration at low dosages and significantly inhibited tumor growth in a nontoxic manner. Furthermore, we provided genome-wide molecular evidence that C-CPE treatment is involved in the stimulation of the ubiquitin-proteasome pathway and the inhibition of cell metabolism in EOC cells., Conclusions: The addition of C-CPE can enhance the effectiveness of Taxol or Carboplatin and significantly inhibited EOC cell growth in a CLDN4-dependent manner, suggesting that C-CPE may have promising therapeutic potential for EOC., (©2010 AACR.)

Safe and effective vaccines against anogenital human papillomaviruses (HPV) are now available. These vaccines, composed of virus-like particles (VLPs) made from the L1 major capsid protein of specific HPV types, induce a polyclonal antibody response directed against specific conformational and linear epitopes displayed on the VLP. Numerous studies indicated the importance of neutralizing antibodies in protection from infection. However, our understanding of the antibody responses to these vaccines is not complete, and there is no established immune correlate of protection nor antibody threshold that correlates with protection against HPV infection or disease. In the current study, antibody responses of young women to Gardasil®, the quadrivalent HPV 6, 11, 16 and 18 L1 VLP vaccine (qHPV), were assessed through 48 months (M) in total IgG and competitive Luminex immunoassays (total IgG LIA and cLIA). The total IgG LIA was developed as a research assay to evaluate preclinical multivalent HPV VLP vaccine formulations. The cLIA simultaneously evaluates the antibody response to a unique conformational, neutralizing epitope on each of the four HPV types present in the quadrivalent vaccine; HPV 6, 11, 16 and 18. The same sera from women vaccinated with the qHPV vaccine were tested in both the total IgG LIA and the cLIA assays. The proportion of vaccinated women achieving seropositivity and the anti-HPV VLP total IgG and cLIA geometric mean titers (GMTs) were summarized at M7, M24, M48 based on the serostatus cut-points defined for each immunoassay. Overall, greater than 99% of subjects seroconverted to all four vaccine types in both assays; GMTs peaked at M7. For all four HPV types, regardless of the immunoassay used, the most significant decline in GMTs was observed between M7 and M24. By M24, the antibody titers had reached a plateau and minimal declines in antibody titers were observed between M24 and M48 for all four HPV types in both immunoassays. Testing the same sera, seropositivity for M48 HPV18 remained high (96.7%) in the total IgG LIA, but was 64.8% in the cLIA. The current study illustrates potential important differences in serologic assays utilized in the clinical trials of the two currently available HPV VLP vaccines (quadrivalent and bivalent). Differences in seropositivity status are attributed to the measurement parameters and sensitivity of the individual immunoassays and do not indicate reduced anti-HPV18 protective antibodies.

Objective: To determine, through a pilot study, whether use of a video-based educational tool can influence overall human papillomavirus (HPV) vaccine acceptability, views on vaccine mandates, school vaccination, and acceptable age for vaccination., Methods: Written surveys addressing HPV knowledge and vaccine acceptability were administered to study participants from January to March 2007. An initial 32-question survey was completed, followed by an 8-minute educational video, and a post-video assessment., Results: Out of 256 subjects, 73.0% watched the video and completed all surveys. Eighty percent of the subjects had heard of HPV, while 65.0% knew, prior to viewing the video, that the vaccine was available. Individual vaccine acceptability increased from 66.7% to 78.0% after the video (p=.0014). Prior to the video, 54.8% of subjects supported mandatory HPV vaccination, with 51.1% supporting school vaccination, and 66.7% accepting vaccination if it were free. After the video, these percentages increased to 72.6% (p<.0001), 65.1% (p<.0001) and 86.6% (p<.0001) respectively. Initially, 56.5% of subjects would vaccinate their child at 15 years of age or younger. After the video, 94.1% approved of vaccination from age 9 (p<.0001). Secondary analysis revealed Hispanics, African Americans, and lower income families were more likely to accept HPV vaccination after the video. A perception that vaccination promotes sex, and whether or not participants talk to their children about sex, did not affect acceptability., Conclusion: Using an educational video significantly increased overall HPV vaccine acceptability and acceptance in younger age groups. This may be an effective means of increasing awareness and acceptability of HPV vaccination., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

This article presents the adolescent clinical trials program for the quadrivalent HPV vaccine (Merck and Co, Inc, Whitehouse Station, NJ) as a case study of the development of a preventive intervention for use in young adolescents to protect against a future sexually transmitted infection and its associated diseases. In light of similarities in Human Papillomavirus (HPV) and HIV with regard to sexual transmission and the associated social and ethical issues related to prevention trial development, lessons learned from the approach taken to the inclusion of adolescents in the quadrivalent HPV vaccine program have potential relevance to future HIV prevention trials. Epidemiologic support for HPV vaccination in adolescents and a regulatory-approved approach to immunogenicity studies for bridging of efficacy from adults formed the basis for including young adolescents in the HPV program. The successful achievement of regulatory approval for use of this prophylactic intervention in young adolescents for prevention of a sexually transmitted infection that is most frequently not acquired before mid to late adolescence required understanding of the particular challenges of studying the vulnerable adolescent population with respect to issues such as federal regulations, the role of parents, confidentiality, empowerment, and retention, and awareness of the social and political context within which prevention interventions are introduced.

Objective: The Hybrid Capture II assay (hc2; QIAGEN, Inc) for high-risk human papillomavirus (hrHPV) is an in vitro nucleic acid hybridization assay using chemiluminescence for the qualitative detection of hrHPV DNA in cervical samples. Results are reported as a ratio of relative light units (RLUs) to a cutoff value based on a positive control. Specimens with RLU ratios of 1.0 or higher are scored positive for hrHPV. We tested the hypothesis that hrHPV positives with low-positive RLU ratios (1-10) had a lower prevalence of cervical intraepithelial neoplasia 2,3 (CIN 2,3) on histologic follow-up., Materials and Methods: Relative light unit ratios for 388 consecutive hrHPV-positive cervical cytologic specimens interpreted as atypical squamous cells of undetermined significance (ASCUS) were reviewed. Individual RLU ratios were compared with outcome histologic diagnosis in cases with colposcopic follow-up and tissue sampling (biopsy and/or endocervical curettage; n = 236)., Results: Of 236 cases with histologic follow-up, 63 had RLU ratios in the range of 1 to 10; of these, 53 (84.1%) were negative for CIN, 7 (11.1%) had CIN 1, 1 (1.6%) had CIN of uncertain grade, and 2 (3.2%) had CIN 2,3. The difference in CIN 2,3 outcome between RLU ratios of 1 to 10 (3.2%) versus over 10 (17.3%) was significant (p =.0047). The difference in prevalence of CIN 1 was not significant (p =.67)., Conclusions: An RLU ratio of 10 or less was associated with a significantly lower prevalence of CIN 2,3 on biopsy outcome after a Pap test result of ASCUS. The much lower prevalence of underlying CIN 2,3 in patients who are weakly HPV-positive may justify modification of the management algorithm for this subset of women with ASCUS.

Objectives: Multinational phase III trials of a human papillomavirus vaccine, Gardasil, have shown the vaccine to be generally well-tolerated, efficacious, and immunogenic. We evaluated the immunogenicity and safety of Gardasil administered concomitantly with Menactra and Adacel., Methods: In this open-label study, boys (n = 394) and girls (n = 648) aged 10 to 17 were randomly assigned in a 1:1 ratio as follows: group A (concomitant administration) received a 0.5-mL dose of Gardasil at day 1, month 2, and month 6 and a 0.5-mL dose of Menactra and Adacel on day 1; group B (nonconcomitant administration) received Gardasil at day 1, month 2, and month 6 and Menactra and Adacel at month 1. Antibody levels for all vaccine components were measured. Systemic, injection-site, and serious adverse experiences (AEs) were monitored., Results: Immune responses after concomitant administration of the 3 vaccines were noninferior to nonconcomitant administration. Seroconversion for Gardasil was > or = 99% in both groups A and B. For Menactra and Adacel, concomitant administration of the vaccines was demonstrated to be noninferior to nonconcomitant administration. Concomitant administration was generally well-tolerated. No participants withdrew because of an AE. One serious AE of transient muscular weakness of <24 hours' duration after the third Gardasil injection was reported in group B and was deemed possibly vaccine-related by the investigator., Conclusions: Overall, concomitant administration was generally well-tolerated and did not interfere with the immune response to the respective vaccines. Concomitant administration should minimize the number of visits required to deliver each vaccine individually, leading to increased compliance and more effective disease prevention.

Objective: To evaluate the subsequent reproductive outcomes in patients with complete and partial molar pregnancy and gestational trophoblastic neoplasia (GTN) at the New England trophoblastic Disease Center between June 1, 1965, and December 31, 2007., Study Design: Questionnaires regarding subsequent pregnancies were mailed to all patients with current mailing addresses at the New England Trophoblastic Disease Center., Results: The subsequent reproductive outcomes in patients with complete and partial molar pregnancies and persistent GTN were in general the same as those in the general population. However, after an episode of molar pregnancy the incidence of molar pregnancy in a later gestation was approximately 1%. Additionally, after successful chemotherapy for GTN, the incidence of stillbirth was 1.4% in later pregnancies., Conclusion: Patients with molar pregnancies and GTN should be reassured that they can in general expect a normal future reproductive outcome.

Objectives: Cervical adenocarcinoma in situ (AIS) is a precursor of invasive disease that is increasing in incidence primarily among reproductive-age women of low parity. Conization is an alternative to hysterectomy that allows future pregnancy, but has an inherent risk of residual AIS. The purpose of this study was to determine the outcomes of patients treated by this fertility-sparing strategy over an extended period of surveillance., Methods: Women diagnosed with cervical AIS who underwent primary fertility-sparing surgery with either loop excision or cold knife conization between 1993 and 2001 were identified at three institutions. A retrospective medical record review was performed. Patients 40 years of age and older and those undergoing hysterectomy within 12 months of diagnosis were excluded., Results: A total of 101 women underwent cone biopsy and expectant management. The median age was 29 years. Fifty-seven percent were nulliparous and 23% primiparous. Cold knife conization was most commonly performed (69 vs. 32 procedures) and had a higher efficacy of achieving negative margins (72% vs. 47%; P=0.036). Thirty-five women had a total of 49 pregnancies during a mean follow-up of 51 months. Thirty-five gestations were delivered at term. There were two preterm births, eight spontaneous miscarriages, three elective terminations, and one ectopic pregnancy. Thirty-six patients had a repeat cone biopsy. Five ultimately underwent hysterectomy. No invasive cervical adenocarcinomas were observed during the study interval., Conclusion: Fertility-sparing surgery enables women with cervical AIS to achieve pregnancy with minimal risk of developing invasive disease during surveillance.

Objective: Unlike other histological types of epithelial ovarian carcinoma, ovarian clear cell carcinoma is known to have very poor response to therapy even when discovered in its early stages. Since tumor hypoxia has been shown to be strongly associated with poor prognosis, deregulation of the representative factor of tissue hypoxia; hypoxia-inducible factor 1 alpha (HIF-1alpha) and related protein; Von Hippel-Lindau (VHL) may be associated with poor prognosis of ovarian clear cell carcinoma., Methods: Immunolocalization of both HIF-1alpha and VHL was performed on 56 cases of paraffin-embedded tissue sections of four different histological types of epithelial ovarian carcinoma and 5 cases of benign ovarian tumors as a control. Quantitative RT-PCR analysis of both HIF1A and VHL was performed on RNA isolated from 61 microdissected frozen tissues of four different histological types of epithelial ovarian carcinoma and 6 cases of normal ovarian epithelial cells. Expression levels of HIF-1alpha and VHL in different histological types and correlation between HIF-1alpha and VHL were determined by nonparametric analysis by Kruskal-Wallis and Spearman's test., Results: HIF-1alpha expression levels were significantly higher in ovarian clear cell carcinoma than in other histological types (P=0.001). We found no correlation between mRNA and protein expression level in any type of carcinoma specimens. Among endometrioid, serous, and mucinous carcinoma, there were no differences in HIF-1alpha expression (P=0.643). There was a negative correlation between HIF-1alpha and VHL in serous (r=-0.661, P=0.027) and in endometrioid carcinoma (r=-0.657 P=0.039), but no correlation was found between HIF-1alpha and VHL expression levels in ovarian clear cell carcinoma (P=0.60)., Conclusions: The results suggest that the role of hypoxia may change according to the histological type of ovarian carcinoma. High expression of HIF-1alpha and its independence from VHL in ovarian clear cell carcinoma may confer chemoresistance in this histological type.

Background: Claudin-4, a tight junction (TJ) protein and receptor for the C-terminal fragment of Clostridium perfringens enterotoxin (C-CPE), is overexpressed in epithelial ovarian cancer (EOC). Previous research suggests DNA methylation is a mechanism for claudin-4 overexpression in cancer and that C-CPE acts as an absorption-enhancing agent in claudin-4-expressing cells. We sought to correlate claudin-4 overexpression in EOC with clinical outcomes and TJ barrier function, investigate DNA methylation as a mechanism for overexpression, and evaluate the effect of C-CPE on the TJ., Methods: Claudin-4 expression in EOC was quantified and correlated with clinical outcomes. Claudin-4 methylation status was determined, and claudin-4-negative cell lines were treated with a demethylating agent. Electric cell-substrate impedance sensing was used to calculate junctional (paracellular) resistance (Rb) in EOC cells after claudin-4 silencing and after C-CPE treatment., Results: Claudin-4 overexpression in EOC does not correlate with survival or other clinical endpoints and is associated with hypomethylation. Claudin-4 overexpression correlates with Rb and C-CPE treatment of EOC cells significantly decreased Rb in a dose- and claudin-4-dependent noncytotoxic manner., Conclusions: C-CPE treatment of EOC cells leads to altered TJ function. Further research is needed to determine the potential clinical applications of C-CPE in EOC drug delivery strategies.

Hydatidiform mole, a disorder of fertilization, comprises complete and partial molar pregnancy. The pathologic and clinical features of complete and partial mole are well-described. Because of earlier diagnosis, however, the clinical presentation of complete molar pregnancy has significantly changed in recent years. The earlier diagnosis of complete mole is associated with more subtle pathologic findings than later molar pregnancy. The use of immunohistochemical techniques for the detection of maternally imprinted genes as ancillary testing in the diagnosis of complete and partial mole is therefore increasing. Although most molar pregnancies are sporadic, a familial syndrome of recurrent hydatidiform mole has been described. Further research will hopefully lead to identification of the gene defect responsible for this uncommon syndrome. Fortunately, patients with molar pregnancies can generally anticipate normal future reproduction. Close hCG follow-up after molar pregnancy is required to rule out development of postmolar gestational trophoblastic neoplasia. Recent studies suggest that a shorter period of postmolar follow-up may be reasonable for patients with both complete and partial molar pregnancy.

Because early ovarian cancer is generally an asymptomatic process, the majority of cases are diagnosed at a late stage, when they are incurable. A precursor lesion, while thought by many to exist, has so far not been successfully identified. While CA-125 is a useful test for the follow-up of patients with established ovarian cancer, it has not led to earlier detection when used alone as a marker. Similarly, ultrasound, although a sensitive test, is not sufficiently specific to be utilized for screening. The combination of CA-125 and ultrasound is currently being studied and may ultimately prove to be an effective screening method for postmenopausal and high-risk women. Research is also under way to identify markers that have sufficient sensitivity and specificity to be utilized in the screening of asymptomatic women; the hope is to ultimately develop a panel of markers for early detection.

Objective: Adenocarcinoma in situ (AIS) is a precursor of invasive disease that is being more frequently diagnosed during the reproductive years. Few reports have described the treatment of this condition in gravid women. The purpose of this study was to review our collective experience managing cervical AIS during pregnancy., Study Design: Retrospective medical record review of all women diagnosed with AIS during pregnancy from 1995 to 2004 at 3 academic institutions., Results: Eleven women with a median age of 32 years were identified. Five who received a diagnosis in the early second trimester underwent uncomplicated cold knife conization (CKC) at 14 to 19 weeks' gestation. Six patients underwent postpartum CKC. All 11 women delivered at term. One patient undergoing postpartum CKC required radical hysterectomy for stage IB1 cervical adenocarcinoma. Four subsequent pregnancies occurred among patients having fertility-sparing surgery., Conclusion: Management of cervical AIS during pregnancy by early second trimester CKC is safe for mother and fetus.

Background: Patients with arteriovenous malformations (AVMs) are at risk for significant vaginal hemorrhage, and are traditionally managed surgically. In the patient desiring future fertility, conservative management via selective arterial embolization is a reasonable option. Only a few cases have been previously reported of successful pregnancy after this procedure in the setting of gestational trophoblastic disease (GTD)., Case: A 31-year-old gravida 1 para 0 was treated for persistent gestational trophoblastic tumor after a complete mole in 1997. She presented with heavy vaginal bleeding, and arteriogram demonstrated a large uterine AVM. The patient underwent selective uterine artery embolization with complete resolution of bleeding, as well as arteriographic cessation of flow through the AVM. After two first-trimester spontaneous abortions, the patient successfully completed a normal pregnancy, resulting in the forceps-assisted delivery of a healthy female infant., Conclusion: Successful term pregnancy can occur after selective uterine artery embolization in women hemorrhaging from symptomatic GTD-associated AVM.

Because some studies have linked polymorphic variants of the estrogen-metabolizing genes CYP17 and catechol O-methyl transferase (COMT) with risk for hormonally related cancers, we sought to determine whether selected polymorphisms of these genes differed between women with and without ovarian cancer. From a population-based study of ovarian cancer, we analyzed DNA from a total of 480 cases and controls. PCR amplification was performed using primers that amplify restriction sites for MspAI (A2 polymorphism-CYP17) and NlaIII (Val/Met polymorphism-COMT). Digestion of the PCR products was performed. Genotypes identified by gel electrophoresis were assigned as homozygous wild type (WW), heterozygous variant (Wv), and homozygous variant (vv). Frequencies were compared using chi(2) or Fisher's exact tests. Logistic regression was used to calculate crude and adjusted relative risks (RRs) for ovarian cancer associated with possession of any variant allele overall, and within demographic, weight, and smoking history categories, and by histological subtype of ovarian cancer. A portion (68.9%) of cases either carried or was homozygous for the A2 variant of CYP17 compared with 53.9% of controls, for a RR (and 95% confidence interval) of 1.86 (1.26, 2.75; P = 0.003), adjusted for age, parity, oral contraceptive use, site of study, and family history of breast or ovarian cancer. The increased risk was most apparent for women >50 and women with invasive serous cancers. A portion (71.9%) of cases either carried or was homozygous for the Val/Met variant of COMT, compared with 76.9% of controls (P = 0.27). Although the inverse association of ovarian cancer with possession of a Val/Met variant was not significant overall, it was for mucinous tumors of the ovary, with an adjusted RR of 0.28 (0.13, 0.61; P = 0.0012). Possession of the A2 variant of CYP17 appears to increase risk for ovarian cancer, whereas possession of the Val/Met variant of COMT decreases the risk for mucinous tumors. Confirmation in other populations and further exploration of potential pathogenetic mechanisms will be necessary.

Modern therapy for molar pregnancy and gestational trophoblastic tumors has resulted in high cure rates and preservation of fertility, even in the setting of metastatic disease requiring chemotherapy. Patients and their partners facing future pregnancy after treatment for gestational trophoblastic disease express fear related to risk of disease recurrence and outcome of subsequent pregnancies. Data from the New England Trophoblastic Disease Center on later pregnancies following complete and partial mole as well as persistent gestational trophoblastic tumor show that patients, in general, can anticipate normal subsequent pregnancy outcomes.

Background: Trophoblastic pulmonary embolization usually occurs after evacuation of a molar pregnancy when the uterus is larger than dates and the human chorionic gonadotropin level is > 100,000 mIU/mL. It has a dramatic onset, with dyspnea, tachypnea, bilateral pulmonary infiltrates and low Po2 levels. Treatment requires supportive measures only. Intubation is rarely required. The clinical course is short-lived, with gradual improvement after 48 hours and complete resolution in 72 hours. There are no long-term sequelae. Differential diagnosis includes pulmonary embolization, fluid overload and aspiration., Case: A 27-year-old, Caucasian woman, gravida 4, para 2, spontaneous abortion 1, developed presumed trophoblastic pulmonary embolization following abdominal hysterectomy for an invasive mole. The clinical course was typical of this condition, with spontaneous clearing in 72 hours with supportive measures only., Conclusion: Trophoblastic pulmonary embolization can occur following abdominal hysterectomy for invasive mole as well as after molar evacuation and should be considered part of the differential diagnosis if patients present postoperatively with acute respiratory distress.