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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. 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. 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. 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.

Estrogen receptor alpha (ER-alpha) is an important regulator of growth and differentiation in the mammary gland and the female reproductive tract. It is also involved in the development of malignant tumors. The human ER-beta is highly homologous to the extensively studied human ER-alpha. It binds to the endogenous 17beta-estradiol with similar affinity as ER-alpha and the transcriptional activity through the consensus ERE can be stimulated. Five ER-beta isoforms were cloned and characterized. They diverge at a common position within the predicted helix 10 of the ligand-binding domain of the human ER-beta, with nucleotide sequences consistent with different exon usage. These isoforms of human ER-beta show differential expression in tissues and in tumor cell lines. Furthermore, they are predicted to form DNA-binding heterodimers when coexpressed. Expression of some of the ER-beta isoforms in human breast tissue, breast cancer, and breast cancer cell lines were reported by several groups. However, there is no complete analysis of the gene expression pattern of all ER-beta isoforms in breast cancer so far. In this study, we examined the mRNA expression of each of the ER-beta isoforms in 30 tumors from breast cancer patients and 21 breast cell lines. In conclusion, expression of ER-beta1, ER-beta2, and ER-beta5 were observed in different cell lines as well as in the tumors, ER-beta4 isoform was expressed in all samples, and ER-beta3 isoform was not detected in any of the samples examined. There were no associations of the expression of all ER-beta isoforms with the invasiveness of the cell lines as well as with clinical parameters of the tumors.

Human papillomaviruses are an important cause of genital warts and cervical cancer. In this large, randomized, placebo-controlled trial, a quadrivalent HPV vaccine given at day 1, month 2, and month 6 was found to significantly reduce the occurrence of cervical intraepithelial neoplasia and vulval or vaginal perianal lesions. No beneficial effect was observed on prevalent lesions. The benefit for prevention of incident lesions associated with HPV-16 and HPV-18 appears to increase with time. A quadrivalent HPV vaccine was found to significantly reduce the occurrence of cervical intraepithelial neoplasia and vulval or vaginal perianal lesions. Anogenital infection with the human papillomavirus (HPV) can cause warts, intraepithelial neoplasia, and invasive cancers. 1 – 6 The majority of HPV-associated diseases are caused by HPV types 6, 11, 16, and 18. HPV types 6 (HPV-6) and 11 (HPV-11) cause most anogenital warts, a portion of the cases of low-grade neoplasia, 5 , 7 – 10 and recurrent respiratory papillomatosis, a rare but potentially life-threatening disease. 11 – 13 HPV type 16 (HPV-16) is the most common cause of invasive cancers of the cervix and other anogenital cancers associated with HPV. 4 , 6 , 14 – 19 HPV type 18 (HPV-18), the second most common cause of cervical cancer, . . .

The invasive potential of tumor cells is usually tested either by in vitro invasion assays which evaluate cell spreading ability in basement membrane-like matrices or by in vivo invasion assays in nude mice. Both methods are laborious and time-consuming. Tumor invasiveness is accompanied by the changes in expression of various genes. The invasive behavior of cells is therefore represented by certain gene expression patterns. The purpose of this study was to investigate whether expression patterns of several genes are characteristic for the invasiveness of cultured cells. We examined the mRNA levels of estrogen receptor (ER), progesterone receptor (PR), estrogen inducible pS2 and plasminogen activator inhibitor-1 (PAI-1) in 23 cell lines derived from benign and malignant breast tissues using a competitive reverse transcription-polymerase chain reaction (cRT-PCR) system. We also evaluated the invasiveness of these cell lines by their ability to penetrate into a collagen-fibroblast matrix. We demonstrate that the gene expression pattern of breast cell lines is clearly associated with their in vitro invasiveness. In general, cells with ER, PR, pS2 but no PAI-1 expression showed a non-invasive phenotype, while cells expressing PAI-1 mRNA but not ER mRNA are invasive. Our study indicates that the invasiveness of breast cancer cell lines is characterized by PAI-1 gene expression and the lack of ER mRNA. This suggests that PAI-1 may participate in the invasive process.

The efficacy of the quadrivalent Human Papillomavirus (HPV) vaccine is thought to be mediated by humoral immunity. We evaluated the correlation between quadrivalent HPV vaccine-induced serum anti-HPV responses and efficacy. 17,622 women were vaccinated at day 1, and months 2 and 6. At day 1 and at 6–12 months intervals for up to 48 months, subjects underwent Papanicolaou and genital HPV testing. No immune correlate of protection could be found due to low number of cases. Although 40% of vaccine subjects were anti-HPV 18 seronegative at end-of-study, efficacy against HPV 18-related disease remained high (98.4%; 95% CI: 90.5–100.0) despite high attack rates in the placebo group. These results suggest vaccine-induced protection via immune memory, or lower than detectable HPV 18 antibody titers.

Cell migration is essential in many diverse processes ranging from embryonic development to wound healing and immune response. Cancer cells have recently been shown to utilize chemoattraction mechanisms mediated by chemokines and their respective receptors, e.g., the CXCL12/CXCR4 pathway normally found in leukocytes. Here we show that Slit2, a secreted protein signaling through the Roundabout (Robo) receptor as a chemorepellent in axon guidance and neuronal migration, acts as a potent chemoattractant for breast cancer cells. Comparing cell lines specifically metastasizing to either brain or bone, we found significant differences in their responses to CXCL12 and Slit2 treatments, suggesting a role for Slit/Robo signaling in brain metastasis.

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.

Recent evidence attributed important influence of chemokines and their receptors on motility, homing, and proliferation of cancer cells at specific metastatic sites. Here we report that the CXCL12 (SDF-1alpha) chemokine receptor CXCR4 is expressed in human ductal carcinoma in situ (DCIS) as well as in atypical ductal hyperplasia. CXCR4 was expressed in pure DCIS and DCIS with concurrent invasive disease. In 66% of the samples, atypical ductal hyperplasia was present, and > 92% exhibited positive CXCR4-staining. Expression of CXCR4 at this very early step of tumor development indicates a role of this receptor in providing a selective advantage to such cells on their way to metastasizing carcinomas. These results strengthen the ideas to target chemokine networks involved in tumor progression and metastatis as a therapeutic approach in malignant disease or as a chemoprevention strategy, blocking the transition from premalignancy to malignancy.

The link between higher uptake of isoflavones and a reduced frequency of menopause-related hot flushes were first described in 1992 based on a lower incidence of hot flushes in countries with high dietary soy intake1. Since then, a number of clinical trials with different sources of isoflavones, including soy and red clover, have been performed, and in almost all studies with an appropriate design the outcome was in favour of isoflavone supplementation2. A detailed risk assessment3 revealed that a number of data in humans do not confirm the alleged adverse effect resulting from possible interaction between isoflavones and the hormone-sensitive tissues of the mammary glands, uterus and thyroid. Safety was demonstrated by long-term intake of 150 mg of isoflavones per day, which lasted at least three years. It was also found that a high intake of isoflavones prevented the occurrence of breast cancer4-7. Clinical findings indicate potential benefits of exposure to isoflavones during breast cancer treatment with tamoxifen or anastrozole.

The link between higher uptake of isoflavones and a reduced frequency of menopause-related hot flushes were first described in 1992 based on a lower incidence of hot flushes in countries with high dietary soy intake1. Since then, a number of clinical trials with different sources of isoflavones, including soy and red clover, have been performed, and in almost all studies with an appropriate design the outcome was in favour of isoflavone supplementation2. A detailed risk assessment3 revealed that a number of data in humans do not confirm the alleged adverse effect resulting from possible interaction between isoflavones and the hormone-sensitive tissues of the mammary glands, uterus and thyroid. Safety was demonstrated by long-term intake of 150 mg of isoflavones per day, which lasted at least three years. It was also found that a high intake of isoflavones prevented the occurrence of breast cancer4-7. Clinical findings indicate potential benefits of exposure to isoflavones during breast cancer treatment with tamoxifen or anastrozole.