Camilla Natter

Treatment of cervical intraepithelial neoplasia with topical imiquimod: a randomized controlled trial.

OBJECTIVE: Alternatives to surgical therapy are needed for the treatment of high-grade cervical intraepithelial neoplasia (CIN 2–3). We aimed to estimate the efficacy of a treatment with imiquimod, a topical immune-response modulator, in patients with CIN 2–3. MATERIALS AND METHODS: Fifty-nine patients with untreated CIN 2–3 were randomly allocated to a 16-week treatment with self-applied vaginal suppositories containing either imiquimod or placebo. The main outcome was efficacy, defined as histologic regression to CIN 1 or less after treatment. Secondary outcomes were complete histologic remission, human papillomavirus (HPV) clearance, and tolerability. Assuming a two-sided 5% significance level and a power of 80%, a sample size of 24 patients per group was calculated to detect a 35% absolute increase in CIN 2–3 regression. RESULTS: Histologic regression was observed in 73% of patients in the imiquimod group compared with 39% in the placebo group (P=.009). Complete histologic remission was higher in the imiquimod group (47%) compared with the placebo group (14%) (P=.008). At baseline, all patients tested positive for high-risk HPV. Human papillomavirus clearance rates were increased in the imiquimod group (60%) compared with the placebo group (14%) (P<.001). In patients with HPV-16 infection, complete remission rates were 47% in the imiquimod group compared with 0% in the placebo group (P=.003). Microinvasive cancer was observed in three of 59 (5% [1–14%]) patients, all within the placebo group. Topical imiquimod treatment was well tolerated, and no high-grade side effects were observed. CONCLUSION: Topical imiquimod is an efficacious and feasible treatment for patients with CIN 2–3. CLINCAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00941252. LEVEL OF EVIDENCE: I

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.

Association of TAP Gene Polymorphisms and Risk of Cervical Intraepithelial Neoplasia

Background. Transporter associated with antigen processing (TAP) is responsible for peptide loading onto class I major histocompatibility complex (MHC-I) molecules. TAP seems to facilitate the detection of HPV by MHC-I molecules and contributes to successful eradication of HPV. TAP polymorphisms could have an important impact on the course of HPV infection. Objective. The aim of this study is to evaluate the association between five TAP gene polymorphisms and the risk of CIN. Methods. This case-control study investigated five common TAP polymorphisms in TAP1 (1341 and 2254) and TAP2 (1135, 1693, and 1993) in 616 women with CIN and 206 controls. Associations between gene polymorphisms and risk of CIN were analysed by univariate and multivariable models. The combined effect of the five TAP gene polymorphisms on the risk for CIN was investigated by haplotype analysis. Results. No significant difference in genotype distribution of the five TAP polymorphisms was observed in women with CIN and controls. Haplotype analysis revealed that women with haplotype mut-wt-wt-wt-wt (TAP polymorphisms t1135-t1341-t1693-t1993-t2254) had a significantly lower risk for CIN, compared to women with the haplotype wt-wt-wt-wt-wt (P = 0.006; OR 0.5 [0.35–0.84]). Conclusion. Identification of this haplotype combination could be used to identify women, less susceptible for development of CIN following HPV infection.

Distinctive outcome in patients with non-uterine and uterine leiomyosarcoma

BackgroundLeiomyosarcomas represent the largest subtype of soft tissue sarcomas. Two subgroups can be distinguished, non-uterine (NULMS) and uterine leiomyosarcomas (ULMS). The aim of this retrospective study was to evaluate differences in clinical features and outcome between these two subgroups.MethodsOutcome and clinical-pathological parameters between 50 patients with NULMS and 45 patients with ULMS were assessed, and compared between both groups. Univariate and multivariable survival analyses were performed.ResultsPatients with ULMS presented with larger tumors when compared to patients with NULMS (p < 0.001). More patients with ULMS initially presented with metastatic disease (67% vs. 36%, p = 0.007). Most common metastatic site was lung for both subtypes (28% and 38%). Five-year overall survival (OS) rates of 82.6% and 41.2% and median OS times of 92.6 (range: 79.7-105.4) and 50.4 (range: 34.8-66.0) months were observed in patients with NULMS and ULMS, respectively (p = 0.006). In multivariate analysis, initial metastatic disease remained an independent prognostic factor in terms of OS (p < 0.0001).ConclusionAt time of diagnosis ULMS were larger and more often metastasized. Therefore patients with ULMS showed unfavorable outcome when compared to NULMS. Later diagnosis might be caused by differences in symptoms and clinical presentation or a more aggressive biological tumor behavior.

Vascular endothelial growth factor gene polymorphisms and risk of cervical intraepithelial neoplasia.

Objective: To evaluate the association between 3 vascular endothelial growth factor (VEGF) gene polymorphisms and susceptibility of cervical intraepithelial neoplasia (CIN). Materials and Methods: This prospectively collected case-control study investigates three common VEGF gene polymorphisms (ie, VEGF −460 [rs833061], VEGF +405 [rs2010963], and VEGF +936 [rs3025039]) in 203 women with CIN and 209 healthy women by DNA pyrosequencing. Associations between polymorphisms and CIN risk are evaluated with univariate and multivariable models and haplotype analysis. Results: In a multivariable regression model, the variant VEGF +405C allele was associated (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.2-5.1], P = 0.02) with increased susceptibility of CIN independent of number of sexual partners (OR, 2.2; 95% CI, 1.1-4.6; P = 0.03) and smoking (OR, 3.3; 95% CI, 1.6-6.6; P = 0.001). The haplotype VEGF −460C - +405C - +936C was associated with an OR of 5.2 (95% CI, 1.2-52.7) for the susceptibility of CIN. Conclusions: The presence of the variant VEGF +405C allele and the haplotype VEGF −460C - +405C - +936C are independently associated with higher susceptibility of CIN.

The Prognostic Value of C-Reactive Protein Serum Levels in Patients with Uterine Leiomyosarcoma

Objective C-reactive protein (CRP) has previously been shown to serve as a prognostic parameter in women with gynecologic malignancies. Due to the lack of valid prognostic markers for uterine leiomyosarcoma (ULMS) this study set out to investigate the value of pre-treatment CRP serum levels as prognostic parameter. Methods Data of women with ULMS were extracted from databases of three Austrian centres for gynaecologic oncology. Pre-treatment CRP serum levels were measured and correlated with clinico-pathological parameters. Univariate and multivariable survival analyses were performed. Results In total, 53 patients with ULMS were included into the analysis. Mean (SD) CRP serum level was 3.46 mg/dL (3.96). Solely, an association between pre-treatment CRP serum levels and tumor size (p = 0.04) but no other clinic-pathologic parameter such as tumor stage (p = 0.16), or histological grade (p = 0.07), was observed. Univariate and multivariable survival analyses revealed that CRP serum levels (HR 2.7 [1.1–7.2], p = 0.037) and tumor stage (HR 6.1 [1.9–19.5], p = 0.002) were the only independent prognostic factors for overall survival (OS) in patients with ULMS. Patients with high pre-treatment CRP serum levels showed impaired OS compared to women with low levels (5-year-OS rates: 22.6% and 52.3%, p = 0.007). Conclusion High pre-treatment CRP serum levels were independently associated with impaired prognosis in women with ULMS and might serve as a prognostic parameter in these patients.

Antiestrogenic effects of the fetal estrogen estetrol in women with estrogen-receptor positive early breast cancer.

Estetrol (E4) is a fetal estrogen with estrogenic effects on reproductive organs and bone in preclinical models and in postmenopausal women. However, E4 exerts antiestrogenic effects on breast cancer (BC) cell growth in vitro and in vivo. We have investigated the effect of 14 days preoperative treatment with 20mg E4 per day on tumor proliferation markers, sex steroid receptor expression and endocrine parameters in a prospective, randomized, placebo-controlled, preoperative window trial in 30 pre- and post-menopausal women with estrogen-receptor positive early BC. E4 had a significant pro-apoptotic effect on tumor tissue, whereas Ki67 expression remained unchanged in both pre- and post-menopausal women. E4 increased sex-hormone-binding globulin significantly thereby reducing the concentrations of bioavailable estradiol. Follicle-stimulating hormone levels decreased in postmenopausal women only and luteinizing hormone levels remained unchanged. Systemic insulin growth factor-1 levels decreased significantly. Intratumoral epithelial ERα expression decreased significantly and a trend was found towards an increased expression of ERβ. This clinical data support the preclinical findings that E4 has antiestrogenic effects on BC cells, whereas earlier studies have shown that E4 has estrogenic effects on reproductive tissues and bone. Further clinical studies seem acceptable and are needed to confirm the safety and efficacy of E4 for the breast in hormone replacement therapy, including hormone replacement therapy in women who have or have had BC, especially in those BC patients treated with aromatase inhibitors and suffering from serious complaints due to estrogen deficiency.

Treatment of Cervical Intraepithelial Neoplasia With Topical Imiquimod: A Randomized Controlled Trial

5041 Background: Alternatives to surgical therapy are needed for the treatment of high-grade cervical intraepithelial neoplasia (CIN). We investigated the effectiveness of a treatment with imiquimod (IMQ), a topical immune-response modulator, for patients with CIN 2 and 3. METHODS In this placebo-controlled trial 59 patients with CIN 2 and 3 were randomized to receive either a 16-week treatment with topical IMQ or placebo. The main outcome was effectiveness, defined as histologic regression (to CIN1 or less) four weeks after end of treatment; secondary outcomes were complete histologic remission, human papillomavirus (HPV) clearance and treatment tolerability. RESULTS Of the patients 27 (46%) and 32 (54%) presented with CIN 2 and 3, respectively. Histologic regression was significantly increased in the IMQ group (75%) compared to the placebo group (41%) (P=0.01). Complete histologic remission was significantly increased in the IMQ group (46%) as compared with the placebo group (15%) (P=0.02). At baseline, all 59 patients (100%) were tested positive for HPV DNA. HPV clearance rate was increased in the IMQ group (61%), as compared with the placebo group (15%) (P<0.001). The lesion progressed to micro-invasive cancer in 2 of 59 patients (3%)-both within the placebo group. Topical IMQ treatment was well tolerated. Due to local and/or systemic side effects, eight patients (27%) within the IMQ group switched to 50%-dose medication and one patient (3%) prematurely quit the treatment. CONCLUSIONS Topical IMQ is an effective treatment for high-grade CIN and is well tolerated.

Die prognostische Bedeutung des Östrogen Rezeptor Regulators PELP1 im Ovarialkarzinom

Fragestellung: Proline- Glutamic acid- and leucine-rich protein (PELP) 1, ist ein bekannter Mediator der Wirkungen der Ostrogen-Rezeptoren und ein potentielles Proto-Onkogen in hormonabhangigen Malignomen. Wir haben die Expressionsmuster und die prognostische Bedeutung von PEPL1 gemeinsam mit den Ostrogen Rezeptoren alpha und beta in Frauen mit Ovarialkarzinom evaluiert. Methode: Die Proteinexpressionslevels wurden mittels immunhistochemischer Farbungen fur Ostrogen Rezeptor alpha und beta sowie fur PELP1 erhoben. Von 63 Patientinnen mit epithelialem Ovarialkarzinom, die zwischen 1996 und 2001 an der Universitatsklinik fur Frauenheilkunde der Medizinischen Universitat Wien operiert wurden, konnte Tumorgewebe aus der Primaroperation fur diese Studie gewonnen werden. Um eine homogene Auswertung zu ermoglichen, wurden Tissue Microarrays hergestellt. Ergebnisse: Die nukleare Expression von PELP1 konnte in 76% der Tumore und allen histologischen Subtypen nachgewiesen werden. Die PELP1 Expression in muzinosen (37,5%) Tumoren war signifikant geringer als in serosen (85,7%) und endometrioiden (86,7%) Tumoren (p=0,015). Es gab eine signifikante Assoziation zwischen PELP1 und Ostrogen Rezeptor beta Expression (p=0,010). PELP1 Expression hatte univariat einen positiven signifikanten Einfluss auf das progressionsfreie- (HR 0,24, p=0,004) und das Gesamtuberleben (HR 0,37, p=0,036). Das gemeinsame Expressionsmuster von Ostrogen Rezeptor beta und PELP1 hatte in einer multivariaten Cox-Regressionsanalyse sogar den starksten unabhangigen Einfluss auf das progressionsfreie- (HR 0,25, p=0,004) und das Gesamtuberleben (HR 0,27, p=0,005). Patientinnen mit doppelt positivem Expressionsmuster hatten ein signifikant besseres Uberleben. Schlussfolgerung: Die Expression des im Ovarialkarzinom noch wenig beforschten Ostrogen Rezeptor Regulators PELP1, alleine und in Kombination mit dem Ostrogen Rezeptor beta, ist ein positiver pradiktiver Faktor fur das progressionsfreie- und das Gesamtuberleben.