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Estetrol (E4) is a pregnancy-specific D-ring metabolite of estradiol (E2) and estriol (E3) produced by the human fetal liver and present in both male and female fetuses. In adults, female exposure is restricted to the gestational period. We report that E4, dose-dependently, prevents the growth of chemically induced (7,12-dimethylbenz(a)anthracene, DMBA) mammary tumors in female Sprague-Dawley rats and that E4 has the potential to reduce the number and size of pre-existing mammary tumors. We performed two prevention studies and one intervention study. In the prevention studies, we investigated the effect of oral doses of E4 over a dose range of 0.5-3.0 mg/kg. The intervention study used oral dose levels of 1, 3 and 10 mg/kg E4. The antiestrogen tamoxifen was used as reference compound in all three studies and ovariectomy and ethinylestradiol, at estrogenic doses pharmacologically equipotent to E4, acted as control treatments in the second prevention study and in the intervention study. Rats treated with DMBA develop estrogen-responsive breast tumors. This model has become the standard pharmacological model to investigate the effect of new compounds on breast tumors. When DMBA-induced rats were co-treated with E4 for 8 weeks, this resulted in a dose-dependent reduction in the number and size of tumors, an effect that appeared equally effective as tamoxifen treatment or ovariectomy and was not seen with ethinylestradiol. When E4 was administered to rats in which tumors had already developed, a significant decrease in the number and size of tumors was observed after 4 weeks. This decrease was dose-dependent, comparable to tamoxifen-treated animals, and at high dose levels E4 was as effective as ovariectomy. [ABSTRACT FROM AUTHOR]

Background: Climacteric symptoms such as hot flushes and vaginal dryness are very common in breast cancer patients, resulting either from age or adjuvant therapy. Tibolone, a synthetic steroid, is effective in reducing these symptoms in healthy post-menopausal women, but this has never been studied in a large breast cancer population.Objectives: The primary objective of LIBERATE trial was to study safety of tibolone 2.5mg daily versus placebo as primary, in symptomatic breast cancer survivors. The aim of this present paper was to report effects of tibolone on climacteric symptoms, vaginal dryness and health-related quality of life in the study population. This trial is registered with ClinicalTrials.gov, n. NCT00408863.Methods: The trial was conducted between June 2002 and July 2007. Concerning quality of life variables, a daily Diary Cards during the first three months and the Climacteric Symptoms Form and at each visit were used to register frequency and intensity of hot flushes. Mean vaginal dryness scores were calculated on the basis of individual ratings at baseline and at week 104. A subset of patients assessed their quality of life filling in the Women's Health Questionnaire (WHQ).Results: Of the 3148 women recruited, 3133 received trial medication (1575 in the tibolone group and 1558 in the placebo group). The median duration of treatment was 2.75 years. In total 3098 women (1556 on tibolone, 1542 on placebo) were included in the intention-to-treat (ITT) population for efficacy analysis. Data on vaginal dryness are available for 2144 patients and 883 women (438 on tibolone, 445 on placebo) answered to WHQ. The mean change in number of hot flushes per day was 2.74 (43.1%) in the tibolone group and -1.77 (-27.5%) in the placebo group (p<0.0001) at week 12 and -4.62 (-65.6%) on tibolone as compared to -3.73 (-52.5%) on placebo (p<0.0001) at week 104. For the composite score the mean changes at week 12 were -0.19 (-10.6%) and -0.14 (-7.7%), respectively (p=0.0006). Vaginal dryness score improved at week 104 in the tibolone group as compared to placebo (-0.46 versus -0.29, respectively; p<0.0001). Across the assessments up to two years with WHQ, tibolone was more effective than placebo in improving sexual health, sleep quality and mood domains. Women using tamoxifen showed less improvement in climacteric symptoms with tibolone, than women only receiving tibolone without any adjuvant therapy.Conclusion: The results of the LIBERATE trial show that tibolone is effective in symptomatic breast cancer patients and improves their quality of life. However, this finding should be judged within the context of the main outcome of the trial, showing that tibolone increases the risk of recurrence. The use of tibolone in women with breast cancer will remain contraindicated and any off-label use incurs a now proven risk. [ABSTRACT FROM AUTHOR]

Aims: The presence of laminated, calcified extracellular debris known as psammoma bodies is a well-known histomorphological feature of ovarian adenocarcinomas and other human malignancies. Biomineralization has recently been found to be associated with a group of extremely small Gram-negative bacteria capable of precipitating calcium salts. The aim of the present study was to evaluate a possible pathogenic link between the development of psammoma bodies and nanobacteria infection. Material and results: Immunohistochemical staining and reverse transcriptase-polymerase chain reaction (RT-PCR) were used to analyse nanobacterial protein and gene expression in eight psammona body-containing adenocarcinomas and in 10 malignant ovarian tumours without signs of biomineralization. Nano-bacterial proteins were detected in eight out of eight (100%) psammoma-positive tumour samples. Conversely, none of the 10 psammoma-negative tissues (0%) was positive for nanobacterial antigens. Furthermore, nanobacterial mRNA was detectable in all of the four tissues (100%) that contained psammoma bodies, but was absent in all 10 ovarian cystadenocarcinomas (0%) that were psammoma negative. Conclusions: We found a 100% concordance between the expression of nanobacteria and the presence of psammoma bodies in malignant ovarian tumours. Several lines of evidence suggest the involvement of these organisms in the process of biomineralization. We therefore conclude that nanobacterial infection of malignant ovarian tissue contributes to mechanisms leading to the formation of calcified deposits known as psammoma bodies. [ABSTRACT FROM AUTHOR]

GSCHWANTLER-KAULICH D., RIEGLER-KEIL M., RUECKLINGER E., SINGER C.F., SEIFERT M. & KUBISTA E. (2011) European Journal of Cancer Care 20, 627-631 Factors influencing the identification rate of the sentinel node in breast cancer Sentinel node biopsy is a widely accepted alternative to primary axillary lymph node dissection for ipsilateral nodal assessment in breast cancer. We have performed a retrospective chart review in 713 consecutive patients with primary, operable breast cancer who underwent sentinel node biopsy in order to identify factors that determine the sentinel node identification rate. Chi-squared test, univariate and multivariate analyses were used to evaluate the influence of different factors on the sentinel identification rate. Among the factors investigated, tumour size was correlated with sentinel lymph nodes detection rates (multiple logistic regression, P= 0.002). In addition, the patient's age showed to be a significant influencing factor (multiple logistic regression, P= 0.006). Body mass index and grade only exhibited a significant correlation with the identification rate in the univariate ( P= 0.041, P= 0.025), but not in the multivariate analysis ( P= not significant). All associations were found to be independent of the site of injection. Interestingly, surgeons with intermediate expertise (11-20 prior dissections) had the highest detection rates ( P= 0.004). We conclude that sentinel identification rates are higher in larger tumours and in younger patients, independent of the injection site. Surgical experience in sentinel node dissection is not linearly correlated with higher identification rates. [ABSTRACT FROM AUTHOR]

Objective Aromatase inhibitors are essential as endocrine treatment for hormone receptor-positive postmenopausal breast cancer patients. Menopausal symptoms are often aggravated during endocrine treatment. We investigated whether vaginal estriol is a safe therapeutic option to overcome the urogenital side-effects of aromatase inhibitors. Serum hormone levels were used as the surrogate parameter for safety. Methods Fasting serum hormone levels of ten postmenopausal breast cancer patients receiving aromatase inhibitors were prospectively measured by electro-chemiluminescence immunoassays and gas chromatography/mass spectrometry before and 2 weeks after daily application of 0.5 mg vaginal estriol (Ovestin®® ovula), respectively. Results Two weeks of daily vaginal estriol treatment did not change serum estradiol or estriol levels. However, significant decreases in levels of serum follicle stimulating hormone ( p == 0.01) and luteinizing hormone ( p == 0.02) were observed. Five out of six breast cancer patients noticed an improvement in vaginal dryness and/or dyspareunia. Conclusions The significant decline in gonadotropin levels, indicating systemic effects, has to be kept in mind when offering vaginal estriol to breast cancer patients receiving an aromatase inhibitor. [ABSTRACT FROM AUTHOR]

BRCA1 mutation carriers are at high risk for breast cancer (BC). The risk management strategy may include radiological investigations for early detection or prophylactic mastectomy (PM). For a mutation carrier, PM may be more significant than surveillance alone when pre-malignant and malignant changes occur increasingly in mastectomy specimens, given normal findings on radiological investigations. In the present study we retrospectively investigated the differences between histological findings in PM specimens of BRCA1 carriers and those of a control group. Twenty-four healthy and 28 affected carriers in the presence of normal preoperative radiological findings were included in the study. To compare the frequency of pre-malignant and malignant lesions in PM specimens, a control group matched for age and disease status was included. T-tests for independent samples and Wilcoxon’s signed-rank test were used for comparison of groups. The entire study group differed significantly from the control group (42.3 vs. 5.8%; P < 0.001) in terms of the occurrence of pre-malignant and malignant lesions. Both, the sub-group comparison of healthy mutation carriers as well as diseased carriers with their controls, showed a significant difference in terms of the occurrence of pre-malignant and malignant changes (45.8 vs. 0%; P = 0.002; 39.3 vs. 10.7%; P = 0.03). In PM specimens of mutation carriers, carcinomas were identified in 5.8% (3/52) and pre-malignant changes in 36.5% (19/52). BRCA1 mutation carriers should be informed of the fact that pre-malignant and even malignant changes are frequently found in PM specimens despite normal radiological findings. [ABSTRACT FROM AUTHOR]

BACKGROUND: The Austrian Breast and Colorectal Cancer Study Group trial-12 (ABCSG-12) bone substudy assesses zoledronic acid for preventing bone loss associated with adjuvant endocrine therapy and reports on long-term findings of bone-mineral density (BMD) during 3 years of treatment and 2 years after completing adjuvant treatment with or without zoledronic acid. The aim of this substudy is to gain insight into bone health in this setting. METHODS: ABCSG-12 is a randomised, open-label, phase III, 4-arm trial comparing tamoxifen (20 mg/day orally) and goserelin (3.6 mg subcutaneously every 28 days) versus anastrozole (1 mg/day orally) and goserelin (3.6 mg subcutaneously every 28 days), both with or without zoledronic acid (4 mg intravenously every 6 months) for 3 years in premenopausal women with endocrine-responsive breast cancer. This prospective bone subprotocol measured BMD at 0, 6, 12, 36, and 60 months. The primary endpoint of the bone substudy (secondary endpoint in the main trial) was change in BMD at 12 months, assessed by dual-energy X-ray absorptiometry in assessable patients. Analyses were intention to treat. Statistical significance was assessed by t tests. The ABCSG-12 trial is registered on the ClinicalTrials.gov website, number NCT00295646. FINDINGS: 404 patients were prospectively included in the bone substudy and randomly assigned to endocrine therapy alone (goserelin and anastrozole or goserelin and tamoxifen; n=199) or endocrine therapy concurrent with zoledronic acid (goserelin, anastrozole, and zoledronic acid or goserelin, tamoxifen, and zoledronic acid; n=205). After 3 years of treatment, endocrine therapy alone caused significant loss of BMD at the lumbar spine (-11.3%, mean difference -0.119 g/cm(2) [95% CI -0.146 to -0.091], p<0.0001) and trochanter (-7.3%, mean difference -0.053 g/cm(2) [-0.076 to -0.030], p<0.0001). In patients who did not receive zoledronic acid, anastrozole caused greater BMD loss than tamoxifen at 36 months at the lumbar spine (-13.6%, mean difference -0.141 g/cm(2) [-0.179 to -0.102] vs -9.0%, mean difference -0.095 g/cm(2) [-0.134 to -0.057], p<0.0001 for both). 2 years after the completion of treatment (median follow-up 60 months [range 15.5-96.6]), patients not receiving zoledronic acid still had decreased BMD at both sites compared with baseline (lumbar spine -6.3%, mean difference -0.067 g/cm(2) [-0.106 to -0.027], p=0.001; trochanter -4.1%, mean difference -0.03 g/cm(2) [-0.062 to 0.001], p=0.058). Patients who received zoledronic acid had stable BMD at 36 months (lumbar spine +0.4%, mean difference 0.004 g/cm(2) [-0.024 to 0.032]; trochanter +0.8%, mean difference 0.006 g/cm(2) [-0.018 to 0.028]) and increased BMD at 60 months at both sites (lumbar spine +4.0%, mean difference 0.039 g/cm(2) [0.005-0.075], p=0.02; trochanter +3.9%, mean difference 0.028 g/cm(2) [0.003-0.058], p=0.07) compared with baseline. INTERPRETATION: Goserelin plus tamoxifen or anastrozole for 3 years without concomitant zoledronic acid caused significant bone loss. Although there was partial recovery 2 years after completing treatment, patients receiving endocrine therapy alone did not recover their baseline BMD levels. Concomitant zoledronic acid prevented bone loss during therapy and improved BMD at 5 years. [ABSTRACT FROM AUTHOR]

Intratumoral estradiol levels in postmenopausal women with breast cancer are thought to be mainly regulated by the aromatase-mediated conversion from androgens and estrogen sulfotransferase (EST)-mediated reduction of bioavailability. While in invasive breast cancer (IBC) the role of both enzymes has been extensively studied and has led to the use of aromatase inhibitors as a key therapeutic strategy, comparably little is still known about their role in the local regulation of estradiol in ductal carcinoma in situ (DCIS). We have performed immunohistochemistry to investigate the expression of aromatase and sulfotransferase in custom-made breast cancer tissue arrays containing 96 samples of pure DCIS and in 104 tumor biopsies which contain both, DCIS and invasive components. We found that aromatase was equally detectable in epithelial components of both, DCIS and IBC ( P = 0.884, Chi square test). However, stromal aromatase expression was significantly higher in IBC compared to adjacent DCIS components ( P = 0.034, Chi square test). Whereas no significant difference was observed for epithelial aromatase expression in high versus non-high grade DCIS ( P = 0.735 Chi square test), epithelial EST levels were found to be significantly down-regulated in high-grade DCIS compared to non-high grade cases ( P = 0.042). We have demonstrated the presence of both aromatase and EST in malignant epithelium and adjacent stromal fibroblasts in DCIS. Lower stromal aromatase expression in preinvasive breast cancer and lower EST levels in high-grade DCIS suggest that the net effect of intratumoral estradiol (E2)-modulating enzymes results in lower local E2 levels in earlier stages of breast tumorigenesis. [ABSTRACT FROM AUTHOR]

Endometriosis is an estrogen-dependent gynecological disease causing pelvic pain and infertility. Impaired estrogen metabolism is thought to play a pivotal role in the pathogenesis of the disease. While there is some information on factors involved in the synthesis of E2, information on E2-deactivating enzymes is still very limited. To elucidate the intracrinology of endometriotic tissues, the authors analyze the expression of aromatase and E2-inactivating estrogen sulfotransferase (EST) in paired biopsies obtained simultaneously from the endometrium and from endometrial lesions of each of 35 patients with peritoneal or ovarian endometriosis and in cycling endometria from 33 women without endmetriosis. Protein localization was demonstrated by immunohistochemistry. Aromatase expression was found in endometriotic glands in 32 of 35 cases and was elevated in comparison to corresponding uterine endometria (25 of 35 cases, P =. 021, ) X² test). The difference was even more pronounced when uterine endometria from endometriosis patients were compared with that of healthy controls (8 of 33 cases, P < .001, X² test). The EST levels were essentially unchanged. The elevated expression of aromatase in eutopic and ectopic endometrium from patients with endometriosis in the presence of comparable EST provides further evidence for unopposed local biosynthesis of estrogens in endometriosis. [ABSTRACT FROM AUTHOR]

To assess the effects of tibolone on climacteric symptoms, endometrium and serum lipid/lipoproteins in postmenopausal women receiving tamoxifen after surgery for breast cancer.Double-blind, randomised, placebo-controlled, multicentre pilot study.Hospital outpatient clinic.Seventy postmenopausal women receiving tamoxifen following surgery for early breast cancer.Women received 20 mg/day oral tamoxifen plus either 2.5 mg/day oral tibolone or placebo for 12 months.Frequency and severity of hot flushes (diary cards); intensity of hot flushes and sweats (Landgren scale); interference of hot flushes and sweats with normal life; frequency and intensity of other climacteric symptoms; endometrial thickness and histology; vaginal bleeding; breast cancer recurrence and serum lipid/lipoproteins.Daily card data showed no change in the daily number of hot flushes with either tibolone or placebo (P= 0.219) after three months. There was a significant reduction in the severity of flushes with tibolone compared with placebo (−0.4vs0.2,P= 0.031). The Landgren scale showed a mean change in the number of hot flushes of−0.6 with tibolone and+1.1 with placebo after 12 months (P= 0.022). Endometrial biopsies were normal and vaginal bleeding was similar in both groups. A significant decrease in triglycerides (−23%vs1.4%) and HDL (−12%vs19%) was seen with tibolone compared with placebo after 12 months.Tibolone prevented an increase in hot flushes in postmenopausal women given tamoxifen following surgery for breast cancer without untoward effects on the endometrium. Beneficial effects on serum lipid profile were noted. [ABSTRACT FROM AUTHOR]

Objective. Human papillomavirus (HPV) infection is the most important event in the malignant transformation of human cervical epithelium. Several high-risk (HR-)HPV subtypes have been identified, which lead to CIN and subsequently to invasive carcinoma. The reason for this phenomenon is still unknown, but it seems to be related to the physical state of HPV DNA.Methods. Digene HC II test was used to identify HR- and/or low-risk (LR-)HPV infections in cervical swabs of 275 women attending our clinic for routine cytological screening and/or colposcopy because of an abnormal Pap smear comprising low-grade squamous intraepithelial lesions (LGSIL) and high-grade SIL (HGSIL). Specific HR (16, 18, 31, 33, 52b, 58) and LR (6, 11) subtypes were characterized in cervical biopsies of 10 women with benign cellular changes and of 68 women with CIN I–III by the PCR-restriction enzyme method. The physical state of HPV DNA (episomal, mixed and integrated form) was analyzed by bi-dimensional (2D)-gel electrophoresis. In addition, mRNA expression of E6/E7 genes was analyzed by RT-PCR. Furthermore, the relative virus load was determined in nine selected cases. The physical state and transcriptional activity of HPV DNA were then correlated to histopathological results.Results. LR-HPV infection [27 cases (9.8%)] and HR-HPV infection [121 cases (44%)] of cervical swabs were clearly correlated to the degree of SIL. Further HPV typing in cervical biopsies of 78 women showed that HPV6 and 11 were restricted to benign cellular changes, CIN I and II, whereas HPV16 and 18 were observed predominantly in CIN III/CIS (P = 0.01). No clear distribution pattern was observed for HPV31, 33, 52b and 58. Expression of HPV E6 and E7 transcripts was uniformly correlated with the different physical state of HPV DNA. Analyzing the physical state of these HPV subtypes, HPV6 and 11 could only be detected as an episomal form, independent of SIL grade. In normal epithelium and in CIN I and II, HPV16 and 18 were exclusively found in the episomal form. In CIN III/CIS, 15 of 30 cases of HPV16 (50%) and 16 of 17 cases of HPV18 (94%) were exclusively integrated into the host genome. Like HPV16/18, HPV31, 33, 52b and 58 were also present in the episomal form in normal epithelium and in CIN I and II, but were integrated in 80% of the CIN III/CIS (4/5) cases.Conclusion. Absent integration of HPV16 DNA in some CIN III/CIS suggests that integration is not always required for progression early dysplastic lesions. In contrast, integration of HPV type 18 and others appears to be of major importance for the transforming efficacy of cervical dysplasia. The applied method represents a sensitive instrument to assess the physical state of HPV and is useful to predict the progression of disease. [Copyright &y& Elsevier]

Objectives. The interleukin-1 system is known to play a pivotal role in human physiology and reproduction. In the cycling endometrium, interleukin-1α activity is controlled by sex steroids and is confined to the perimenstrual phase, where it is involved in the events leading to tissue lysis and menstruation. Since local tissue degradation is also a feature of malignant tumors, our goal was to analyze the gene expression of interleukin-1α and other interleukin-1 family members and compare it with estrogen receptor α, estrogen receptor β, and progesterone receptor mRNA expression in 27 endometrial carcinomas and 13 normal endometria.Methods. Endometrial tumor tissues were obtained during hysterectomy for endometrial cancer, and normal endometrium was sampled in women undergoing surgical procedures for nonendometrial pathologies. Gene expression was analyzed by reverse transcription polymerase chain reaction. Protein expression was detected and localized by immunohistochemical staining.Results. A strong gene expression of interleukin-1 type I receptor, estrogen recptor α, and progesterone receptor was detected in all tumor tissues and in the majority of benign endometrial tissues. However, in contrast to nonmalignant endometria, variable amounts of interleukin-1β and interleukin-1 receptor antagonist mRNA were also detected in most of the tumor samples. Gene expression of interleukin-1α and estrogen receptor β was considerably less frequent, with interleukin-1α being absent in all peri- and postmenopausal endometria and in all but one of the well-differentiated tumors. With decreasing differentiation interleukin-1α gene expression became more frequent. In these cases, interleukin-1α protein was detected predominantly in epithelial tumor cells of lower-grade tumors.Conclusion. We have demonstrated the presence of the interleukin-1 system in endometrial malignancies, and found a negative correlation between interleukin-1α and tumor differentiation. We hypothesize that the nonphysiological expression of interleukin-1α in less differentiated tumors might contribute to their invasiveness and malignant behavior. [Copyright &y& Elsevier]

ABSTRACT Objective The main arteries to the breast are the lateral thoracic artery and to a lesser extent the internal thoracic artery. In this prospective open diagnostic study involving 94 women, we compared the intraindividual differences of Doppler indices in the lateral thoracic (breast-feeding) artery of breasts affected by cancer with those unaffected by disease. Methods Sixty-seven consecutive patients were recruited from an outpatient unit for breast surgery and 27 volunteers were studied who were known to be without any breast disease (controls). In each patient we attempted to obtain Doppler indices from the lateral thoracic artery of both breasts. The difference in Doppler indices in each individual was assessed and statistical analysis was performed to assess whether these differences were significantly altered in women with cancer compared to healthy women. Results Lateral thoracic arteries could be visualized in 88% of the study population. Significantly lower values for pulsatility and resistance indices and systolic/diastolic ratios were obtained in the lateral thoracic arteries of breasts affected by cancer as compared to the contralateral breasts (1.73 ± 0.39 vs. 2.05 ± 0.47, P = 0.003; 0.78 ± 0.06 vs. 0.84 ± 0.06, P < 0.0001; 4.71 ± 1.24 vs. 6.75 ± 3.38, P = 0.0008, respectively). Using the intraindividual difference of pulsatility index, resistance index and systolic/diastolic ratio to screen for malignancy, sensitivities for breast cancer of 78%, 85% and 83%, respectively, were achieved. Depending on the cut-off level, specificity reached 94%. Conclusion The intraindividual difference in Doppler indices in women with breast cancer may be a useful test for the diagnosis of breast lesions. [ABSTRACT FROM AUTHOR]