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Women from ethnic minority groups, including immigrants and refugees are reported to have low breast cancer (BC) screening rates. Active, culturally-sensitive outreach is vital for increasing participation of these women in BC screening programs. Women at high BC risk and who belong to an ethnic minority group are of special concern. Such women could benefit from ongoing trials aimed at optimizing screening strategies for early BC detection among those at increased BC risk. Considering the marked disparities in BC survival in Europe and its enormous and dynamic ethnic diversity, these issues are extremely timely for Europe. We systematically reviewed the literature concerning European surveillance studies that had imaging in the protocol and that targeted women at high BC risk. The aim of the present review was thereby to assess the likelihood that women at high BC risk from minority ethnic groups were adequately included in these surveillance programs. Twenty-seven research groups in Europe reported on their imaging surveillance programs for women at increased BC risk. The benefit of strategies such as inclusion of magnetic resonance imaging and/or more intensive screening was clearly documented for the participating women at increased BC risk. However, none of the reports indicated that sufficient outreach was performed to ensure that women at increased BC risk from minority ethnic groups were adequately included in these surveillance programs. On the basis of this systematic review, we conclude that the specific screening needs of ethnic minority women at increased BC risk have not yet been met in Europe. Active, culturally-sensitive outreach is needed to identify minority women at increased BC risk and to facilitate their inclusion in on-going surveillance programs. It is anticipated that these efforts would be most effective if coordinated with the development of European-wide, population-based approaches to BC screening.

Cervical cancer is the second most common cancer among women in Argentina and the mortality rate is not declining despite opportunistic screening. Free-of-charge human papillomavirus (HPV) vaccination of 11-year-old girls was introduced in 2011. Parental acceptance of HPV vaccination is considered to be of great importance for HPV vaccine uptake. However, little is known regarding this factor in Argentina. The aim of the present study was to explore maternal HPV vaccination acceptance, willingness to pay for HPV vaccination and correlates of this willingness, awareness of HPV and HPV-associated disease and behaviors and attitudes associated with HPV vaccination acceptance. A total of 180 mothers of girls aged 9-15 years comprised this quantitative, cross-sectional, survey-based study, conducted at two hospitals in the Mendoza Province. Correlates of willingness to pay for HPV vaccination were obtained using multivariable logistic regression models. Maternal HPV vaccination acceptance was 90%, and 60% of mothers were willing to pay for HPV vaccination. Mothers who were gainfully employed and had a higher disposable household income were significantly more willing to pay for HPV vaccination [odds ratio (OR)=2.54, 95% confidence interval (CI) 1.01-6.38; OR=3.28, 95% CI 1.36-7.94, respectively], as were mothers who were aware of cervical cancer prior to the study (OR=3.22, 95% CI 1.02-10.14). Only one in 10 mothers were informed that HPV vaccination does not offer complete protection against cervical cancer. In conclusion, the present study showed high maternal HPV vaccination acceptance, although acceptance decreased when vaccination was not free-of-charge. Continuous public education campaigns are needed to improve knowledge of HPV, HPV vaccines and HPV-associated disease.

A prospective clinical study was carried out to investigate whether endometrial microvessels in patients with idiopathic heavy menstrual bleeding (HMB) of endometrial origin (HMB-E) are fragile due to low pericyte coverage. Idiopathic HMB-E is characterized by large endothelial cell gaps related to the microvascular overexpression of vascular endothelial growth factor (VEGF)-A and VEGF receptors 1-3. A total of 10 women with a normal menstrual cycle and a history of HMB of <5 years, and 17 healthy women with a normal menstrual cycle were recruited from the Karolinska University Hospital. Blood samples were obtained for hormone analysis and coagulation tests. Endometrial biopsies were collected in the proliferative or in the secretory phase. Pericyte coverage was assessed using immunohistochemical staining for smooth muscle actin-α (SMAα) and by image analysis (microvascular density) of endometrial biopsies from 10 patients with HMB-E and 17 healthy ovulating women (control subjects). Previously published data on endothelial cell gap size and the expression of VEGF receptors were used. Although microvascular density did not differ between the patients with HMB-E and the control subjects, the number of SMAα-positive microvessels in the proliferative phase was significantly (P=0.005) lower in the patients with HMB-E than in the control subjects. Moreover, the number of SMAα-positive microvessels in the control subjects was significantly fewer in the secretory (P=0.04) than in the proliferative phase, whereas this number did not differ among the patients with HMB-E regardless of phase. A significant negative correlation was observed between the number of VEGF-A-positive microvessels and microvessels with pericyte coverage (r=0.8; P=0.04). Finally, the endothelial cell layer was significantly thicker in the patients with HMB-E than in the control subjects. Thus, the upregulation of VEGF-A in idiopathic HMB-E is associated with a low pericyte coverage during the proliferative phase of intense angiogenesis, which may confer vessel fragility, possibly leading to excessive blood loss.

Cervical cancer is the second most prevalent malignancy among women worldwide, and additional objective diagnostic markers for this disease are needed. Given the link between cancer development and alternative splicing, we aimed to analyze the splicing patterns of the PRDX2, RAB1A, RAB1B, RAB5A and RAB25 genes, which are associated with different cancers, in normal cervical tissue, preinvasive cervical lesions and invasive cervical tumors, to identify new objective diagnostic markers. Biopsies of normal cervical tissue, preinvasive cervical lesions and invasive cervical tumors, were subjected to rapid amplification of cDNA 3' ends (3' RACE) RT‑PCR. Resulting PCR products were analyzed on agarose gels, gel‑purified and sequenced. Normal cervical tissue, preinvasive cervical lesions and invasive cervical tumors contained one PCR product corresponding to full‑length PRDX2, RAB5A and RAB25 transcripts. All tissues contained two RAB1A‑specific PCR products corresponding to the full‑length transcript and one new alternatively spliced RAB1A transcript. Invasive cervical tumors contained one PCR product corresponding to the full‑length RAB1B transcript, while all normal cervical tissue and preinvasive cervical lesions contained both the full‑length RAB1B transcript and three new alternatively spliced RAB1B transcripts. Alternative splicing of the RAB1A transcript occurs in all cervical tissues, while alternative splicing of the RAB1B transcript occurs in normal cervical tissue and in preinvasive cervical lesions; not in invasive cervical tumors.

Transforming growth factor-β (TGFβ) and epidermal growth factor (EGF) are two potent regulators of tumorigenesis. Signaling cross-talk of TGFβ and EGF employs a number of regulators which define the impact on cell physiology. MST1 has recently been reported as a regulator of tumorigenesis and differentiation. To investigate the role of mammalian sterile-like 1 (MST1) in TGFβ and EGF signaling, we established transiently MST1‑transfected HEC-1-A endometrial cancer cells, and subjected the cells to treatment with TGFβ1, EGF and their combination. We report MST1 as a negative regulator of combined TGFβ and EGF signaling. We observed that enhanced expression of MST1 inhibited the combined action of TGFβ1 and EGF on cell invasiveness, migration and proliferation. Monitoring of the intracellular regulatory proteins showed that MST1 contribution to the TGFβ-EGF cross-talk may involve focal adhesion kinase and E-cadherin, but not activation of Smad2. Our data unveiled the role of MST1 as a negative feedback for TGFβ1‑ and EGF‑regulated cell invasiveness, migration and proliferation.

Cervical cancer is the second most common cancer among women in Argentina and the mortality has remained unchanged for the last 30 years. The 2011 national implementation of human papillomavirus (HPV) vaccination will be a key component of future cervical cancer prevention. Vaccination of young adult women is not included in the program, although these women could also benefit from the vaccine, especially in underserved areas with a high prevalence of HPV. However, research on acceptance of HPV vaccination within this group is scarce. The aim of this study was to investigate acceptance of HPV vaccination, the correlation between acceptance and cost, as well as other factors and perceptions of HPV vaccination among young adult women in Argentina. In total, 174 young women aged 18-30 years were included in this quantitative cross-sectional hospital-based study in a low resource area of the Mendoza Province, conducted through structured questionnaire-based interviews. Multinomial logistic regression models were used to investigate correlates of acceptance. Acceptance of HPV vaccination was high if it was free (95%) and even if it was not (75%). A significant positive association was found between acceptance and belief in vaccine safety (p=0.01) and between acceptance and not being a welfare recipient (p=0.00). Nearly half the participants incorrectly believed that they would be fully protected against cervical cancer after vaccination. Our findings suggest that acceptance of HPV vaccination is high among young women in a high-risk, relatively underserved area, even if vaccination is not free. Extensive misconceptions about the vaccine, however, highlight the need for further education about HPV vaccination.

The endometrium goes through a unique cycle of physiological angiogenesis during the normal menstrual cycle (MC). We studied whether there is a correlation between endothelial progenitor cells (EPCs) and plasma and endometrial levels of angiogenic growth factors during the MC. Ten healthy, regularly menstruating women provided blood samples and another 16 supplied endometrial biopsies. Blood samples were obtained over a single MC: twice in the proliferative and once in the secretory phase and at ovulation. Endometrial biopsies were provided in the proliferative or in the secretory phase. We assessed plasma levels of vascular endothelial and fibroblast growth factors, granulocyte and granulocyte-macrophage colony-stimulating factors and stromal cell-derived factor-1 (SDF-1) by ELISA; EPCs by a colony-forming unit (CFU) assay; immunostaining for endometrial SDF-1 by computer-assisted software; and endothelial cell (EC) markers by flow cytometry. In the proliferative phase, SDF-1 levels were significantly higher than during the secretory phase. EPC-CFUs correlated negatively to SDF-1 levels. Endometrial SDF-1 expression tended to be higher in the secretory than in the proliferative phase. Furthermore, vascular endothelial growth factor receptors and Tie-2 EPCs showed a cyclic pattern over the MC. Our results point to SDF-1 as a novel mediator of EPC trafficking during the MC.

Detection of E6/E7 mRNA expression using the real-time nucleic acid sequence-based amplification assay (NASBA) PreTect HPV-Proofer was compared with results of human papillomavirus (HPV) DNA detection in 98 paraffin-embedded samples from patients with cervical adenocarcinoma. HR-HPV DNA was detected in 61 (62%), while HR-HPV E6/E7 mRNA was detected in 63 (64%) of the samples. Correlation between results from DNA analyses and the E6/E7 mRNA assay showed consistent results in 87% of samples (47 of 54). The results from these two methods in detecting presence of HPV infection of any type agreed in 77%. Overall agreement between the methods was seen in 82 of the 98 cases (84%). When evaluating change in sensitivity for detection of HPV positives by adding more HPV types to the HPV DNA assay, maximum sensitivity was reached by targeting four HPV types. The coverage of HPV DNA presence was 76.9%, while the E6/E7 mRNA assay achieved a maximum coverage of 80.8% using only three HPV types. Thus, E6/E7 oncogene expression analysis may provide a more objective test for assessment of neoplastic glandular cells. Further studies may reveal whether the clinical performance of the E6/E7 mRNA assay will be of prognostic value in management of cervical adenocarcinoma.

Aquaporin-1 (AQP1) is involved in the angiogenesis and structural modifications of microvessels and possibly also in the pathogenesis of idiopathic menhorrhagia, where a reduced AQP1 expression is seen in the endometrium. Mifepristone treatment induces reduced menstrual bleeding and amenorrhea and also has a direct effect on endometrial arterioles. Administered with gestagen-only contraceptive methods, antiprogestins improve the bleeding pattern. The objective of this study was to evaluate the AQP1 expression in endometrial blood vessels during normal cycle and after mifepristone treatment. Localization and expression of AQP1 was determined using immunohistochemistry and reverse transcriptase chain reaction (RT-PCR) in 43 biopsies from human endometrium taken during a normal cycle and after mifepristone treatment. AQP1 expression in human endometrial vessels is not cycle dependent and is stronger in capillaries and arteries than in veins. After mifepristone treatment the staining intensity was increased, but not the number of stained vessels. The presence of AQP1 was also confirmed using RT-PCR. The changes in AQP1 expression could contribute to the reduced bleeding seen following mifepristone treatment and could be an effect of either antagonizing progesterone or cortisol.

Angiogenesis is essential for endometrial growth and repair, and disruption of this process may lead to common gynecological disorders, including menorrhagia and endometriosis. We have recently shown that expression of vascular endothelial growth factor (VEGF)-A and its two main receptors, VEGFR-1 and -2, is increased in idiopathic menorrhagia (IM). The aim of this study was to determine the expression of VEGFR-3 in normal and IM endometrium. Endometrial biopsies from 24 patients with IM and 18 healthy and fertile women were used for immunohistochemistry assessments and image analyses of VEGFR-3 and CD34-stained endothelial structures. We found that weak to moderate expression of VEGFR-3 was present in stroma and glands throughout the menstrual cycle without differences between patients and controls. Capillaries expressed VEGFR-3 markedly, whereas arterioles and venules stained moderately to markedly. However, we observed that vascular expression of VEGFR-3 in capillaries was 1.6-fold higher in the IM group than in controls, when assessed as the number of stained capillaries per mm(2). There was also a 2.0-fold higher number of arterioles, which were VEGFR-3 positive in the IM group. There was no difference with regard to the menstrual cycle between patients and controls. Thus, human endometrium expresses VEGFR-3, and expression of this receptor is increased in idiopathic menorrhagia. These results indicate that VEGFR-3 may play a role in the abnormal endometrial angiogenesis of IM.

Aquaporin-1 (AQP1) is a water channel protein expressed in vascular endothelia and involved in impaired angiogenesis in tumors. Since angiogenesis is an essential component of the regeneration of the endometrium, we sought to analyze the expression of AQP1 in endometrial blood vessels in normal cyclic endometrium as well as in endometrial biopsies of menorrhagia patients. Endometrial biopsies from 16 patients with menorrhagia and 21 healthy fertile women were used for immunohistochemistry assessment of AQP1-stained endothelial structures. RT-PCR was used to confirm the presence of AQP1 mRNA. We detected the expression of AQP1 solely in endometrial blood vessels in the control group, as well as in menorrhagic endometrium. There was no difference between proliferative and secretory endometrium. Furthermore, we observed that the vascular expression of AQP1 in endometrial blood vessels in the menorrhagia group was significantly lower than in controls (p=0.002). There was also a significantly lower number of stained vessels per unit area in the menorrhagia group than in the controls (p=0.006). Thus, the deregulation of aquaporin-1 in menorrhagia may be involved in abnormal endometrial vascular growth and permeability.

Detection of E6/E7 mRNA expression with real-time nucleic acid sequence-based amplification assay (NASBA) method (PreTect HPV-Proofer) from high-risk types of human papillomaviruses (HR-HPV) were compared with the presence of viral load, determined with quantitative real-time PCR in 80 cervical samples. Results regarding positivity and typing were in agreement using the two methods. However, there was no correlation between viral loads for HPV 16 or 18/45 and oncogene expression. Among 15 women with low grade atypia detected at a population-based cytology screening, and scored as 'within normal limits' according to histopathology, 14% were positive for oncogene expression, whereas 71% were HR-HPV positive. A correlation was observed between HR-HPV oncogene expression and high scores of p16(INK4a) positivity. Since HPV-Proofer detects full-length E6/E7 mRNA, a positive result should correlate with presence of integrated HPV, loss of HPV replication and stabilized E6/E7 full-length mRNA expression. Such expression from integrated HR-HPV generates a high and stable expression of full-length E6 proteins, which explains why a positive HPV-Proofer result was independent of viral load and correlate with high expression of p16(INK4a). Thus, E6/E7 oncogene expression analysis yielded information, which is consistent with and will complement the results from a real-time PCR method in a clinical prognostic procedure.