Consensus: soy isoflavones as a first-line approach to the treatment of menopausal vasomotor complaints.

The association between an increased uptake of isoflavones and a reduced frequency of menopausal hot flushes was first described in 1992, based on a lower incidence of hot flushes in countries with a high consumption of soy. Since then, numerous clinical trials with various sources of isoflavones including soy and red clover have been presented, with practically all of the studies with adequate design delivering an outcome in favour of isoflavone supplementation. An in-depth risk assessment (EFSA 2015) concludes that the amply available human data does not indicate any suspected harmful effects from a potential interaction of isoflavones with hormone-sensitive tissues in the mammary gland, the uterus and the thyroid gland. Safety was ascertained with long-term intake of up to 150 mg isoflavones per day ingested for the duration of at least 3 years. Moreover, high isoflavone intake was found to have preventive effects with respect to breast cancer. Clinical findings indicate potential benefits of isoflavone exposure even during breast cancer treatment with tamoxifen or anastrozole.

Genetic variations of interleukin-1 and -6 genes and risk of cervical intraepithelial neoplasia.

OBJECTIVE: To evaluate the association between five interleukin-1 (IL-1) and -6 gene polymorphisms and risk of high grade cervical intraepithelial neoplasia (CIN 2-3). METHODS: This case-control study investigates five common IL-1 and IL-6 gene polymorphisms in 131 women with CIN 2-3 and 209 controls by pyrosequencing and polymerase chain reaction. Associations between gene polymorphisms and risk of CIN 2-3 are analysed by univariate and multivariable models. Their combined effect on the risk of CIN is evaluated by haplotype analysis. RESULTS: In a multivariable regression model IL1A -889 (odds ratio 0.3 [95% confidence interval 0.1-0.8], p=0.01) and smoking (4.0 [1.7-9.1], p=0.001) are independently associated with the risk of high grade CIN. Haplotype analysis does not reveal any high-risk combinations for the susceptibility of CIN. CONCLUSION: The single nucleotide polymorphism IL1A -889 is independently associated with risk of high grade CIN.

Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases.

BACKGROUND: A phase 3 trial was conducted to evaluate the efficacy of a prophylactic quadrivalent vaccine in preventing anogenital diseases associated with human papillomavirus (HPV) types 6, 11, 16, and 18. METHODS: In this randomized, placebo-controlled, double-blind trial involving 5455 women between the ages of 16 and 24 years, we assigned 2723 women to receive vaccine and 2732 to receive placebo at day 1, month 2, and month 6. The coprimary composite end points were the incidence of genital warts, vulvar or vaginal intraepithelial neoplasia, or cancer and the incidence of cervical intraepithelial neoplasia, adenocarcinoma in situ, or cancer associated with HPV type 6, 11, 16, or 18. Data for the primary analysis were collected for a per-protocol susceptible population of women who had no virologic evidence of HPV type 6, 11, 16, or 18 through 1 month after administration of the third dose. RESULTS: The women were followed for an average of 3 years after administration of the first dose. In the per-protocol population, those followed for vulvar, vaginal, or perianal disease included 2261 women (83%) in the vaccine group and 2279 (83%) in the placebo group. Those followed for cervical disease included 2241 women (82%) in the vaccine group and 2258 (83%) in the placebo group. Vaccine efficacy was 100% for each of the coprimary end points. In an intention-to-treat analysis, including those with prevalent infection or disease caused by vaccine-type and non-vaccine-type HPV, vaccination reduced the rate of any vulvar or vaginal perianal lesions regardless of the causal HPV type by 34% (95% confidence interval [CI], 15 to 49), and the rate of cervical lesions regardless of the causal HPV type by 20% (95% CI, 8 to 31). CONCLUSIONS: The quadrivalent vaccine significantly reduced the incidence of HPV-associated anogenital diseases in young women. (ClinicalTrials.gov number, NCT00092521 [ClinicalTrials.gov].).

Influence of department volume on survival for ovarian cancer: results from a prospective quality assurance program of the Austrian Association for Gynecologic Oncology.

OBJECTIVE: The Austrian Association for Gynecologic Oncology initiated in 1998 a prospective quality assurance program for patients with ovarian cancer. The aim of this study was to evaluate factors predicting overall survival especially under consideration of department volume. METHODS: All Austrian gynecological departments were invited to participate in the quality assurance program. A questionnaire was sent out that included birth date, histology, date of diagnosis, stage, and basic information on primary treatment. Description of comorbidity was not requested. Patient life status was assessed in a passive way. We did record linkage between each patient's name and birth date and the official mortality data set collected by Statistics Austria. No data were available on progression-free survival. Patients treated between January 1, 1999 and December 31, 2004 were included in the analysis. Mortality dates were available to December 31, 2006. Data were analyzed by means of classical statistical methods. Cut-off point for departments was 24 patients per year. RESULTS: A total of 1948 patients were evaluable. Approximately 75% of them were treated at institutions with fewer than 24 new patients per year. Patient characteristics were grossly similar for both department types. Multivariate analysis confirmed established prognostic factors such as International Federation of Gynecologists and Obstetricians (FIGO) stage, lymphadenectomy, age, grading, and residual disease. In addition, we found small departments (<24 patients per year) to have a negative effect on overall survival (hazards ratio, 1.38: 95% confidence interval, 1.2-1.7; and P < 0.001). CONCLUSIONS: The results indicate that in Austria, rules prescribing minimum department case load can further improve survival for patients with ovarian cancer.

Evaluation of quadrivalent HPV 6/11/16/18 vaccine efficacy against cervical and anogenital disease in subjects with serological evidence of prior vaccine type HPV infection.

OBJECTIVE: In the quadrivalent (types 6/11/16/18) HPV vaccine (GARDASIL/SILGARD) clinical program, 73% of women aged 16-26 were naïve to all vaccine HPV types. In these women, prophylactic administration of the vaccine was highly effective in preventing HPV 6/11/16/18-related cervical disease. Of the remaining women, 15% of had evidence of past infection with one or more vaccine HPV types (seropositive and DNA negative) at the time of enrollment. Here we present an analysis in this group of women to determine the efficacy of the HPV 6/11/16/18 vaccine against new cervical and external anogenital disease related to the same vaccine HPV type which had previously been cleared. Vaccine tolerability in this previously infected population was also assessed. METHODS: 18,174 women were enrolled into 3 clinical studies. The data presented comprise a subset of these subjects (n = 2,617) who were HPV seropositive and DNA negative at enrollment (for >or=1 vaccine type). In each study, subjects were randomized in a 1:1 ratio to receive HPV 6/11/16/18 vaccine or placebo at day 1, month 2 and month 6 (without knowledge of baseline HPV status). Procedures performed for efficacy data evaluation included detailed genital examination, Pap testing, and collection of cervicovaginal and external genital specimens. Analyses of efficacy were carried out in a population stratified by HPV serology and HPV DNA status at enrollment. RESULTS: Subjects were followed for an average of 40 months. Seven subjects in the placebo group developed cervical disease, and eight subjects developed external genital disease related to a vaccine HPV type they had previously encountered. No subject receiving HPV 6/11/16/18 vaccine developed disease to a vaccine HPV type to which they were seropositive and DNA negative at enrolment. CONCLUSIONS: These results suggest that natural HPV infection-elicited antibodies may not provide complete protection over time, however the immune response to the HPV 6/11/16/18 vaccine appears to prevent reinfection or reactivation of disease with vaccine HPV types. Vaccine-related adverse experiences were higher among subjects receiving vaccine, mostly due to increased injection site adverse experiences.

Efficacy of a quadrivalent prophylactic human papillomavirus (types 6, 11, 16, and 18) L1 virus-like-particle vaccine against high-grade vulval and vaginal lesions: a combined analysis of three randomised clinical trials.

BACKGROUND: Vulval and vaginal cancers among younger women are often related to infection with human papillomavirus (HPV). These cancers are preceded by high-grade vulval intraepithelial neoplasia (VIN2-3) and vaginal intraepithelial neoplasia (VaIN2-3). Our aim was to do a combined analysis of three randomised clinical trials to assess the effect of a prophylactic quadrivalent HPV vaccine on the incidence of these diseases. METHODS: 18 174 women (16-26 years) were enrolled and randomised to receive either quadrivalent HPV6/11/16/18 L1 virus-like-particle vaccine or placebo at day 1, and months 2 and 6. Individuals underwent detailed anogenital examination at day 1, 1 month after dose three, and at 6-12-month intervals for up to 48 months. Suspect genital lesions were biopsied and read by a panel of pathologists and vaccine HPV type-specific DNA testing was done. The primary endpoint was the combined incidence of VIN2-3 or VaIN2-3 associated with HPV16 or HPV18. Primary efficacy analyses were done in a per-protocol population. FINDINGS: The mean follow-up time was 3 years. Among women naive to HPV16 or HPV18 through 1 month after dose three (per-protocol population; vaccine n=7811; placebo n=7785), the vaccine was 100% effective (95% CI 72-100) against VIN2-3 or VaIN2-3 associated with HPV16 or HPV18. In the intention-to-treat population (which included 18 174 women who, at day 1, could have been infected with HPV16 or HPV18), vaccine efficacy against VIN2-3 or VaIN2-3 associated with HPV16 or HPV18 was 71% (37-88). The vaccine was 49% (18-69) effective against all VIN2-3 or VaIN2-3, irrespective of whether or not HPV DNA was detected in the lesion. The most common treatment-related adverse event was injection-site pain. INTERPRETATION: Prophylactic administration of quadrivalent HPV vaccine was effective in preventing high-grade vulval and vaginal lesions associated with HPV16 or HPV18 infection in women who were naive to these types before vaccination. With time, such vaccination could result in reduced rates of HPV-related vulval and vaginal cancers.

Expression of the human MTA1 gene in breast cell lines and in breast cancer tissues.

MTA1 was reported as a metastasis-associated gene. Tumors with higher MTA1 mRNA level were shown to have higher rates of invasion and lymph node metastasis and tended to have higher rates of vascular involvement. The majority of invasive breast carcinomas were demonstrated to overexpress MTA1 compared to surrounding normal tissues. MTA1 was also found to be more expressed in metastatic breast cancer cell lines than in nonmetastatic ones. Originally we were interested in analyzing factors differently expressed in invasive and noninvasive breast cancer cell lines. Therefore we analyzed expression of MTA1 together with several other genes in correlation with cell invasiveness in 25 breast epithelial cell lines. Furthermore, we analyzed it in 90 primary breast tumor tissues and examined its correlation with expression of estrogen receptor, progesterone receptor, plasminogen activator inhibitor-1, E-cadherin, histopathological data, disease-free survival, and overall survival. Our results demonstrated that MTA1 expression was significantly higher in noninvasive cell lines than in invasive ones. It also correlated positively with expression of noninvasive factors and reverse correlated with invasive factors in both cell lines and tumor tissues.

Expression of KLF5 is a prognostic factor for disease-free survival and overall survival in patients with breast cancer.

PURPOSE: Kruppel-like factor (KLF5) is a cell growth mediator in various epithelial cells. Higher KLF5 increases cell growth rate and leads to transformed phenotypes. Because tumor cell proliferation is tightly associated with tumor progression, and consequently, with survival of cancer patients, we wanted to examine the prognostic value of KLF5 gene expression for patients with breast cancer. EXPERIMENTAL DESIGN: The gene expression levels of KLF5, ER, PR, HER2, and MKI67 were quantified in the tumor tissues of 90 patients with breast cancer and correlated with disease-free survival and overall survival of the patients. The correlations of gene expression between KLF5 and ER, PR, HER2, and MKI67 were analyzed. In addition, KLF5 expression was also compared with clinical data and age of patients. RESULTS: Statistically significant correlations were found between gene expression of KLF5 and both disease-free survival (univariate analysis) and overall survival (univariate and multivariate analysis). Patients with higher KLF5 expression had shorter disease-free survival and overall survival time, whereas patients with lower KLF5 expression had better survival. Moreover, KLF5 was also found to be positively correlated with HER2 and MKI67, and negatively correlated with age of the patients at diagnosis. CONCLUSION: The gene expression of KLF5 is directly correlated with cell proliferation in vivo and is a prognostic factor for patients with breast cancer. Patients with higher KLF5 expression have shorter disease-free survival and overall survival than patients with lower KLF5 expression. In addition, KLF5 has higher expression in patients ages 50 years old.

Interleukin-1 and interleukin-6 gene polymorphisms and the risk of breast cancer in caucasian women.

PURPOSE: Genetic polymorphisms of cytokine-encoding genes are known to predispose to malignant disease. Interleukin (IL)-1 and IL-6 are crucially involved in breast carcinogenesis. Whether polymorphisms of the genes encoding IL-1 (IL1) and IL-6 (IL6) also influence breast cancer risk is unknown. EXPERIMENTAL DESIGN: In the present case-control study, we ascertained three polymorphisms of the IL1 gene cluster [-889 C/T polymorphism of the IL1alpha gene (IL1A), -511 C/T polymorphism of the IL1beta promoter (IL1B promoter), a polymorphism of IL1beta exon 5 (IL1B exon 5)], an 86-bp repeat in intron 2 of the IL1 receptor antagonist gene (IL1RN), and the -174 G/C polymorphism of the IL6 gene (IL6) in 269 patients with breast cancer and 227 healthy controls using PCR and pyrosequencing. RESULTS: Polymorphisms within the IL1 gene cluster and the respective haplotypes were not associated with the presence and the phenotype of breast cancer. The IL6 polymorphism was significantly associated with breast cancer. Odds ratios for women with one or two high-risk alleles versus women homozygous for the low-risk allele were 1.5 (95% confidence interval, 1.04-2.3; P = 0.04) and 2.0 (95% confidence interval, 1.1-3.6; P = 0.02), respectively. No association was ascertained between presence of the IL6 polymorphism and various clinicopathologic variables. CONCLUSIONS: Although polymorphisms within the IL1 gene cluster do not seem to influence breast cancer risk or phenotype, presence of the -174C IL6 allele increases the risk of breast cancer in Caucasian women in a dose-dependent fashion.

A common polymorphism within the steroid 5-alpha-reductase type 2 gene and timing of menopause in Caucasian women.

OBJECTIVE: Androgens are thought to play an important role in various reproductive functions. We evaluated the association between a common polymorphism of the steroid 5-alpha-reductase type 2 gene (SRD5A2) involved in androgen metabolism and the timing of menopause. STUDY DESIGN: Three hundred and twenty-three consecutive women were included in this cross-sectional study. The common exon 1 Valine/Leucin polymorphism of the SRD5A2 gene was analyzed using a microarray-based system. RESULTS: No significant association between the SRD5A2 polymorphism and age (years) at natural menopause was ascertained. There were no significant differences in the background characteristics of the subjects among SDR5A2 genotypes including the number of full term pregnancies, age at first delivery, BMI, personal or family history of breast cancer, smoking status and personal history of recurrent abortion. A multivariate regression analysis showed that the number of full term pregnancies, but not smoking, an increased body mass index, or a history of breast cancer significantly influenced timing of natural menopause. CONCLUSION: In the present study the number of full term pregnancies, but not the common V89L SRD5A2 polymorphism, is the only significant predictor for the timing of natural menopause in Caucasian women.

An interleukin-6 gene promoter polymorphism influences the biological phenotype of ovarian cancer.

Interleukin (IL)-6 is known to be involved in the pathogenesis of ovarian cancer. We investigated a common G/C polymorphism at position -174 of the IL-6 gene (IL6) promoter in 121 patients with ovarian cancer using pyrosequencing. Presence of at least one mutant allele was associated with early tumor stage as well as an expanded length of disease-free (DFS) and overall survival with a dose-dependent effect regarding the carriage of 0, 1, and 2 alleles. In a multivariate Cox regression model incorporating tumor stage and residual tumor mass, presence of the -174 C allele of IL6 was the best predictor of DFS. We conclude that the mutant -174 C allele of IL6 influences the biological phenotype of ovarian cancer because it is associated with early stage and improved DFS and overall survival.

Characterization of benign and malignant breast lesions with computed tomography laser mammography (CTLM): initial experience.

OBJECTIVES: The aim of this study was to characterize benign and malignant breast lesions with computed tomography-laser mammography (CTLM). MATERIALS AND METHODS: In a prospective study, 100 female patients with 105 breast lesions classified as BIRADS IV to V at mammography underwent mammography, CTLM, and histologic verification at our institution. CTLM images were analyzed by radiologists with knowledge of the lesion's position but who were blinded to histology and morphologic findings from mammography. Two radiologists independently evaluated whether there was increased absorption, a sign of malignancy, on CTLM and assessed the appearance (volumes or linear branching) and shape (round or irregular) of the lesions. RESULTS: Histologic analysis revealed 55 benign (52.4%) and 50 malignant (47.6%) breast lesions. Increased absorption was observed significantly more often in malignant than in benign lesions (70.0% vs. 32.7%, P = 0.028). Invasive cancer showed increased absorption in 76.2%, and ductal carcinoma in situ in 37.5%. Common morphologic characteristics of increased absorption were "volumes" (85.7% of malignant and 77.8% of benign lesions) with round shape (78.1% of malignant and 73.3% of benign lesions). CONCLUSION: Our data indicate that CTLM, when used as an adjunct to mammography, may provide additional information to characterize benign and malignant breast lesions.

HMGA2 is associated with invasiveness but not a suitable marker for the detection of circulating tumor cells in breast cancer.

Previously, the human high mobility group protein member HMGA2 mRNA was reported to be expressed in peripheral blood of patients with breast cancer, but not in healthy individuals. Expression of HMGA2 in blood was suggested to be an independent indicator of poor prognosis in metastatic breast cancer. These very promising findings propose HMGA2 as a potential marker for the detection of circulating tumor cells in peripheral blood. Therefore, we analyzed peripheral blood specimens from healthy controls and patients with breast tumors for HMGA2 expression using TaqMan real-time RT-PCR to test if HMGA2 is a suitable marker for the early detection of breast cancer and monitoring therapy response in peripheral blood. Furthermore, we examined the possible involvement of HMGA2 expression in invasion investigated by an in vitro invasion assay using established breast cell lines. HMGA2 expression was detected in peripheral blood of breast cancer patients as well as of healthy individuals. No significant association of HMGA2 expression with any clinical or histopathological data was apparent. However, there was a significant correlation of HMGA2 expression in invasive and non invasive breast cell lines (p=0.0056). Although, HMGA2 obviously contributes to invasion it is not a specific marker for the detection of circulating tumor cells in peripheral blood.

Vascular endothelial growth factor splice variants and their prognostic value in breast and ovarian cancer.

PURPOSE: Vascular endothelial growth factor (VEGF) is a promotor for tumor angiogenesis, and is known to be elevated in breast and ovarian cancers. Through alternative splicing six VEGF isoforms were identified. We studied VEGF isoform expression in breast and ovarian cancer cell lines, as well as in breast carcinomas and ovarian tumors, and correlated the expression pattern with the in vitro invasiveness of the breast carcinoma cell lines and the clinicopathologic characteristics of the tumors. EXPERIMENTAL DESIGN: Reverse transcription-PCR and automated laser fluorescence fragment analysis were used to determine the expression of each splice variant. This method allowed the detection of all of the splice variants simultaneously, especially VEGF145 for the first time in tumor tissue. RESULTS: VEGF121 and VEGF165 were the most dominantly expressed variants in all of the tumor samples and cell lines investigated. VEGF145 was very weakly or not expressed in breast and ovarian cancers. Statistical analysis showed no correlation between VEGF splice variant expression in the tumors and histological type, differentiation grade, tumor size, Fédération Internationale des Gynaecologistes et Obstetristes, and nodal status from cancer patients. There was also no correlation between the invasive capacity of breast cell lines and VEGF isoform expression. CONCLUSIONS: Even though expression levels of VEGF have been shown to be important for tumor invasion and progression, the present data indicate no relation of VEGF isoform pattern with invasion and progression.

The influence of a Vitamin D receptor gene polymorphism on the timing of female reproductive functions in humans.

OBJECTIVE: To evaluate the association between a common polymorphism of the Vitamin D receptor gene (VDR) and the timing of female reproductive functions in humans. METHODS: One thousand fifty-eight consecutive women were included in this cross-sectional study. We analyzed the intron 8 Bsm I restriction fragment length polymorphism (RFLP) of VDR on chromosome 12q using a microarray-based system. RESULTS: The presence of the VDR polymorphism did not influence the timing of menarche and natural menopause and was not associated with the number of spontaneous abortions, full term pregnancies (FTP) as well as the total number of pregnancies. Of note, women with at least one mutant allele of VDR were at a significantly decreased risk for experiencing surgical menopause (odds ratio [OR] 0.65, 95% confidence interval [CI], 0.46-0.92, P = 0.02). Smoking and a body mass index (BMI) > 25 were associated with an earlier natural menopause and an increased risk for surgical menopause, respectively. CONCLUSIONS: While no association of a common polymorphism of VDR with the timing of menarche and menopause was ascertained, we found the presence of at least one mutant allele of VDR to be associated with a decreased risk of experiencing surgical menopause, i.e., premenopausal hysterectomy, in a large series of Caucasian women.

Genetic alterations in endometrial hyperplasia and cancer.

Putative precursors of endometrial cancer such as complex endometrial hyperplasia with atypia have been described to be monoclonal and considered to be genetically related. In order to identify a genetic marker that could serve as a putative predictor of endometrial cancer we analyzed 14 endometrial hyperplasia and 29 endometrial cancer samples for instabilities and loss of heterozygosity (LOH) in microsatellite sequences. Deletions on the short arm of chromosome 8 were frequently detected in both endometrial hyperplasia and cancer samples, suggesting that these deletions are early events in the development of endometrial cancer.

Role of p53 in G2/M cell cycle arrest and apoptosis in response to gamma-irradiation in ovarian carcinoma cell lines.

We investigated the cell cycle and apoptotic response to irradiation in 4 human ovarian carcinoma cell lines, i.e., PA-1, Caov-3, SK-OV-3, and ES-2. Cell lines were also analysed for their p53 and Bax expression to address the relationship with cell cycle and apoptotic response. Apoptosis was examined by flow cytometric measurement of annexin V binding and by determination of cytoplasmic histone-associated DNA fragments with a photometric enzyme immunoassay. Cell cycle analyses were performed on the basis of flow cytometry. p53 and Bax protein expression was examined by immunocytochemistry in untreated cells and after irradiation. p53 cDNA sequencing and a functional yeast-based assay (FASAY) were performed to determine the p53 mutational status. All cell lines exhibited a dose-dependent G2/M arrest. No arrest in G1 was seen. A strong correlation was found between the G2/M arrest and the induction of apoptosis. PA-1, the only cell line found to express wild-type p53, showed the highest susceptibility to accumulate in G2/M and the strongest apoptotic response after irradiation. In this cell line irradiation resulted in an unequivocal accumulation of p53 protein and in an increased expression of Bax protein. Caov-3, lacking wild-type p53, showed upregulation of Bax expression after irradiation. Caov-3 proved to be relative sensitive to apoptosis compared to SK-OV-3 and ES-2. These two cell lines were found to be p53 mutated in sequence analysis and irradiation had no effect on the expression of p53. No change in Bax expression was seen in ES-2, while SK-OV-3 exhibited decreased Bax protein levels after irradiation. Our data suggest that the G2/M arrest is an important component of the pathway leading from irradiation-induced DNA damage to apoptosis in the examined cell lines. The G2/M arrest and associated apoptosis found in the examined cell lines does not necessarily require wild-type p53, although wild-type p53 and possibly Bax may contribute to a maximum response to irradiation. Two independent mechanisms, p53-dependent and p53-independent, are suggested in the examined cell lines.

The urethra during pelvic floor contraction: observations on three-dimensional ultrasound.

OBJECTIVE: To investigate with three-dimensional ultrasound how voluntary pelvic floor contractions influence the morphology of the female urethra's components. METHODS: Twenty female patients with benign gynecologic disorders (mean age: 29 years; range: 19-40) had transrectal sonography using a 7.5-MHz mechanical sector endoprobe with three-dimensional features during both pelvic floor muscle relaxation and pelvic floor muscle contraction. The multiplanar display of the scanned volumes allowed detailed morphologic assessment of the urethra and the measurement of distances and volumes of the urethral components. Statistical end points were maximum sagittal and transverse urethral diameter, maximum sphincter length and thickness, maximum smooth muscle thickness, and the volumes of the sphincter, the smooth muscle, and the entire urethra. RESULTS: All 20 rectal scans were feasible. Two patients had to be excluded from analysis because of poor image quality, leaving 18 patients for evaluation. When compared with pelvic floor relaxation, the following measures were smaller during pelvic floor contraction: sagittal urethral diameter (10.4 versus 11.5 mm; P =.004), transverse urethral diameter (14.1 versus 15.0 mm; P =.009), urethral sphincter thickness (2.4 versus 2.7 mm; P =.012), urethral sphincter volume (0.5 versus 0.6 mL; P =.003), and total urethral volumes (1.4 versus 1.5 mL; P =.007). Sphincter length and smooth muscle thickness, as well as smooth muscle volume, did not change significantly during pelvic floor contraction. CONCLUSION: On three-dimensional ultrasound, the morphologic changes of the female urethra during pelvic floor contraction suggest external compression of the urethra rather than contraction of the sphincter muscle.

Polymorphisms of the interleukin-1 gene cluster and ovarian cancer.

OBJECTIVE: Interleukin-1 (IL-1) is known to be critically involved in ovarian carcinogenesis. We investigated a panel of polymorphisms of the IL-1 and the IL-1 receptor antagonist (IL-1 RA) genes in patients with ovarian cancer. METHODS: One hundred thirty-four patients with surgically staged ovarian cancer, 27 patients with borderline ovarian cancer, and 134 healthy controls were genotyped for three polymorphisms of the IL-1 gene (-889 C/T polymorphism of the IL-1alpha gene [IL1A], -511 C/T polymorphism of the IL-1beta promoter [IL1B promoter], a polymorphism of IL-1beta exon 5 [IL1B exon 5]), and an 86-base pair repeat in intron 2 of the IL-1 RA gene [IL1RN]) using polymerase chain reaction and pyrosequencing. RESULTS: Allelic frequencies did not differ between patients with ovarian cancer and controls. In the ovarian cancer group, polymorphism did not correlate with any of the investigated clinicopathologic variables, including tumor stage, lymph node, and histologic grade. In univariate and multivariate models, there was no correlation between any polymorphism and patients' overall and disease-free survival. CONCLUSION: We investigated interleukin polymorphisms in ovarian cancer but did not find any association between common polymorphisms of IL1A, IL1B, and IL1RN and the occurrence of ovarian cancer. Allelic variation within the IL-1 gene clusters does not seem to play a role in ovarian carcinogenesis and does not appear to be a useful tool for possible screening and risk evaluation.

Evaluation of MUC1 splice variants as prognostic markers in patients with ductal carcinoma in situ of the breast.

Despite intense research in the field of breast cancer it still remains the most common cancer in women in the Western world. A decreasing trend in mortality was mainly achieved by improved early detection which led to an increased incidence of ductal carcinoma in situ (DCIS) of the breast. For the patient's prognosis and the administration of a patient-tailored therapy strategy it is crucial to identify diagnostic and prognostic markers for high-risk DCIS patients. MUC1 is associated with tumour aggressiveness in human breast cancer. Recent studies used MUC1 splice variant A to identify malignant thyroid cancer. In the present study we have examined the usefulness of MUC1 splice variants as prognostic markers in DCIS. We used laser capture microdissection of paraffin-embedded tissue to isolate RNA from isolated tumour cells and determined the MUC1 splice variant distribution by RT-PCR. In the majority of cases variant B was more highly expressed than variant A. This was true for pure DCIS (66%) as well as for DCIS with adjacent invasive cancer (66%). In 7 out of 18 cases (38%) of pure DCIS variant A was not expressed at all. In DCIS with adjacent invasive cancer only 2 samples out of 12 showed this expression pattern (16%). The situation that variant A was more highly expressed than B, or that variant B was not expressed at all, was similar for pure DCIS (27%) and for DCIS with adjacent invasive cancer (33%). The present study describes the differences of MUC1 splice variant expression in pure DCIS compared to DCIS with adjacent invasive cancer. A discriminating pattern of MUC1 splice variants could not be demonstrated.