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Objective: Because angiogenesis is considered essential for tumor growth and the development of metastasis, we assessed the correlation of microvessel density with overall survival in patients with clinical stage IB carcinoma of the uterine cervix.Study Design: Histologic slides were immunostained for factor VIII-related antigen. Microvessel density was determined within each tumor by enumeration under a light microscope at 200x magnification and an examination area of 0.25 mm2. The Cox proportional hazards model was used for multivariate analysis.Results: In 166 patients with stage IB cervical cancer the 5-year survival was as follows: 89.7% in 102 patients whose tumors had a microvessel density < or =20/field, and 63.0% in 64 patients whose tumors had a microvessel density >20/field (log rank p < 0.0001). In the multivariate Cox model microvessel density, lymph node involvement, tumor size, and the application of radiation therapy remained independent prognostic factors for survival, whereas lymphatic vascular space involvement failed to retain a significant value.Conclusion: High microvessel density adversely influences patients' survival in clinical stage IB cervical cancer and identifies patients with negative nodes at risk for relapse. [ABSTRACT FROM AUTHOR]

We wanted to evaluate the feasibility and effect of a hands-on loop electrosurgical excision procedure (LEEP) 2.5-day intensive surgical skills workshop, using a novel training model on porcine tissue. Hands-on simulation-based training was conducted to emphasize colposcopy, local anesthesia, uterine cervix and vulva punch biopsy, LEEP, and complication management. Performance of 51 participants'' technical skills was assessed before and after training completion. LEEP performance was significantly better after completion of the training (P < .001). Before and after training mean scores (SD) of 18.0 (3.5) and 23.4 (2.1) were assessed. Multivariate analysis revealed that the training effects were independent of previous surgical expertise. The LEEP workshop was feasible and effective and we recommend implementing hands-on LEEP training into gynecology training programs. [Copyright &y& Elsevier]

Objective: The purpose of this study was to evaluate the association between fibrinogen plasma levels on disease-free patients and overall survival in patients with cervical cancer. Study Design: Pretherapeutic fibrinogen plasma levels were examined in 313 patients with cervical cancer who were treated at the Department of Obstetrics and Gynecology, Medical University of Vienna. Fibrinogen plasma levels were correlated with clinical-pathologic findings and patient survival. Results: Mean (± SD) pretherapeutic fibrinogen plasma levels were 417.4 mg/dL (± 130.3 mg/dL). Elevated fibrinogen plasma levels were associated with advanced tumor stage (P < .001) and patient age (P < .001), but not with histologic type (P = .4), histologic grade (P = .1), and pelvic lymph node involvement (P = .9). In a multivariate survival analysis, fibrinogen plasma levels (P < .001 and < .001) and lymph node involvement (P < .001 and = .001), but not patients'' age (P = .8 and .4) and histologic type (P = .7 and .5) were associated with overall or disease-free survival, respectively. Histologic grade was associated with disease-free (P = .01), but not with overall, survival (P = .2). Conclusion: Fibrinogen plasma levels are an independent prognostic parameter in patients with cervical cancer. [Copyright &y& Elsevier]

Abstract: Objective: Hypoalbuminemia, a known marker for malnutrition and increased morbidity and mortality, has been associated with impaired prognosis in different cancer entities. The present study investigates the prognostic value of pre-treatment serum albumin levels for survival in patients with endometrial cancer. Study design: Within the present cohort study, we evaluated 337 consecutive patients with endometrial cancer and investigated the association of pre-treatment serum albumin levels and clinical-pathological parameters. We performed univariate log-rank tests and multivariable Cox regression models to assess the association between pre-treatment serum albumin levels and survival. Results: Pre-treatment serum albumin levels were inversely proportionally associated with FIGO tumor stage, histological grade, and patients’ age. In a multivariable analysis pre-treatment serum albumin levels (p =0.02 and p =0.001), FIGO tumor stage (p <0.001 and p <0.001), and histological grade (p =0.002 and p <0.001) were independently associated with disease-free and progression-free survival, respectively. Conclusion: Pre-treatment serum albumin is a novel and independent prognostic parameter for disease-free and progression-free survival in patients with endometrial cancer. [Copyright &y& Elsevier]

Abstract: Cyclin E, coded by the genes CCNE1 and CCNE2, is the main regulator for transition from G1 to S phase determining cell division. CCNE1 and CCNE2 are known oncogenes in many cancer entities. Especially CCNE1 has frequently been associated with gene amplifications in various malignancies, emphasising its role as a putative oncogene. We determined gene expression and copy number of CCNE1 and CCNE2 by quantitative polymerase chain reaction (PCR) from 172 International Federation of Obstetrics and Gynecology (FIGO) II/III/IV stage serous epithelial ovarian cancer (EOC) tissues and analysed its impact on outcome. Furthermore, whole transcriptome gene expression changes correlating with CCNE1 expression were determined by microarray technology, interpreted by Signalling Pathway Impact Analysis (SPIA), Tool for Inferring Network of Genes (TINGe), and illustrated by hive plots. Protein–protein interaction (PPI) networks were also used for the interpretation. Interestingly, and contradictory to most reports and intuitive expectations, high CCNE1 expression correlated with better overall survival (p =0.005) if corrected for usual clinicopathologic parameters and a molecular subclassification. Using different grading systems or only high graded tumours had no impact on this correlation. Copy number of CCNE1 was increased in 25% of cases which correlated highly significantly with expression but showed no impact on outcome. CCNE2 had no impact on outcomes at all. Whole genome transcriptome analysis revealed 1872 differentially expressed genes correlated to CCNE1 expression, which were significantly enriched with genes from five pathways (e.g. cell cycle and viral carcinogenesis pathway were up-regulated and the Fanconi anaemia pathway was down-regulated). High CCNE1 gene expression is a significant and independent predictor for prolonged overall survival in FIGO III/IV EOC patients. This upside down impact of CCNE1 on survival probably reflects the special characteristic of EOC with tumour dissemination in the near anaerobic peritoneal cavity as the predominant cause of death, compared to other cancer entities where distant metastasis are predominantly lethal. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To investigate the association between plasma fibrinogen levels and clinico-pathological parameters of patients with vulvar cancer and to determine their value as prognostic parameters. Study design: In this retrospective study, we evaluated pretreatment plasma fibrinogen levels in 120 patients with invasive squamous cell vulvar cancer and correlated them with clinico-pathological parameters and patients’ survival. Results: Pretreatment plasma fibrinogen levels were directly associated with tumor stage (pT1a vs. pT1b vs. pT2 vs. pT3-4, p = 0.001), lymph node involvement (pN0 vs. pN1, p = 0.04), and histological grade (G1 vs. G2 vs. G3, p = 0.03), but not with patients’ age (≤70 years vs. >70 years, p = 0.6). In a multivariate survival analysis, tumor stage (p = 0.006/p = 0.02) and lymph node involvement (p < 0.001/p < 0.001), but neither histological grade (p = 0.2/p = 0.9) nor plasma fibrinogen levels (p = 0.6/p = 0.6) were associated with disease-free and overall survival, respectively. In a multivariate analysis, patient''s age (≤70 years vs. >70 years) was associated with overall survival (p = 0.03) but not with disease-free survival (p = 0.1). Conclusion: Pretreatment plasma fibrinogen levels were directly associated with tumor stage, lymph node involvement and histological grade. Although we could demonstrate a prognostic value of pretreatment plasma fibrinogen levels on survival, we were unable to establish fibrinogen as an independent prognostic parameter in patients with vulvar cancer. [Copyright &y& Elsevier]

Objective: To establish the prevalence of endometriosis metastatic to pelvic sentinel lymph nodes (PSLN) in women with ovarian and/or peritoneal endometriosis. Design: Prospective clinical study. Setting: Academic research institution. Patient(s): Women with a laparoscopic diagnosis of ovarian and/or peritoneal endometriosis verified by intraoperative frozen section analysis. Intervention(s): Resection of endometriotic lesions and PSLN after cervical blue dye injection. Main Outcome Measure(s): Histologic analysis of PSLN for the presence of endometriosis and immunohistochemical analysis of estrogen receptor (ER), progesterone receptor (PR), cytokeratin (CK), and CD-10 expression. Result(s): The study enrolled 26 women with suspected endometriosis; endometriosis was confirmed in 23 women, and a PSLN was identified in 19 women. A total of 37 (right side: 20; left side: 17) lymph nodes were removed. The prevalence of endometriotic lesions in PSLN was 11% (2 of 19). Both lesions were positive for ER, PR, CK, and CD-10. Isolated endometriotic-like cells (IELCs) staining positive for ER and PR were identified in the peripheral sinus of 16 (80%) of 20 and 14 (70%) of 20 PSLN, respectively. All IELCs lacked CK staining, whereas CD-10 staining was present in 16 (80%) of 20 cases, indicating a stromal origin of IELCs. Intraoperative and/or postoperative complications were observed in 1 (5%) of 19 women. Conclusion(s): Spread of IELCs to PSLN is common in ovarian and/or peritoneal endometriosis. Metastatic lesions in PSLN are present in 11% of women. Further studies to evaluate the prognostic and predictive value of endometriotic spread to PSLN are warranted. [Copyright &y& Elsevier]

Abstract: Background: To analyse the overall clinical outcome and benefits by applying protocol based image guided adaptive brachytherapy combined with 3D conformal external beam radiotherapy (EBRT)±chemotherapy (ChT). Methods: Treatment schedule was EBRT with 45–50.4Gy±concomitant cisplatin chemotherapy plus 4×7Gy High Dose Rate (HDR) brachytherapy. Patients were treated in the “protocol period” (2001–2008) with the prospective application of the High Risk CTV concept (D90) and dose volume constraints for organs at risk including biological modelling. Dose volume adaptation was performed with the aim of dose escalation in large tumours (prescribed D90>85Gy), often with inserting additional interstitial needles. Dose volume constraints (D2cc) were 70–75Gy for rectum and sigmoid and 90Gy for bladder. Late morbidity was prospectively scored, using LENT/SOMA Score. Disease outcome and treatment related late morbidity were evaluated and compared using actuarial analysis. Findings: One hundred and fifty-six consecutive patients (median age 58years) with cervix cancer FIGO stages IB–IVA were treated with definitive radiotherapy in curative intent. Histology was squamous cell cancer in 134 patients (86%), tumour size was >5cm in 103 patients (66%), lymph node involvement in 75 patients (48%). Median follow-up was 42months for all patients. Interstitial techniques were used in addition to intracavitary brachytherapy in 69/156 (44%) patients. Total prescribed mean dose (D90) was 93±13Gy, D2cc 86±17Gy for bladder, 65±9Gy for rectum and 64±9Gy for sigmoid. Complete remission was achieved in 151/156 patients (97%). Overall local control at 3years was 95%; 98% for tumours 2–5cm, and 92% for tumours >5cm (p =0.04), 100% for IB, 96% for IIB, 86% for IIIB. Cancer specific survival at 3years was overall 74%, 83% for tumours 2–5cm, 70% for tumours >5cm, 83% for IB, 84% for IIB, 52% for IIIB. Overall survival at 3years was in total 68%, 72% for tumours 2–5cm, 65% for tumours >5cm, 74% for IB, 78% for IIB, 45% for IIIB. In regard to late morbidity in total 188 grade 1+2 and 11 grade 3+4 late events were observed in 143 patients. G1+2/G3+4 events for bladder were n =32/3, for rectum n =14/5, for bowel (including sigmoid) n =3/0, for vagina n =128/2, respectively. Interpretation: 3D conformal radiotherapy±chemotherapy plus image (MRI) guided adaptive intracavitary brachytherapy including needle insertion in advanced disease results in local control rates of 95–100% at 3years in limited/favourable (IB/IIB) and 85–90% in large/poor response (IIB/III/IV) cervix cancer patients associated with a moderate rate of treatment related morbidity. Compared to the historical Vienna series there is relative reduction in pelvic recurrence by 65–70% and reduction in major morbidity. The local control improvement seems to have impact on CSS and OS. Prospective clinical multi-centre studies are mandatory to evaluate these challenging mono-institutional findings. [Copyright &y& Elsevier]

Objective: To evaluate gene expression signatures of breast tissue in female-to-male (FtM) transsexuals under cross-sex hormone therapy (HT). Design: Prospective cohort study. Setting: Academic research institution. Patient(s): Five hormone-naïve FtM transsexuals before and after HT. Intervention(s): Breast tissue biopsy before and after 2 years of intramuscular testosterone undecanoate (1,000 mg every 12 wk) and oral lynestrenole (5 mg daily), and gene signature analysis by global gene expression array covering 28,869 genes. Main Outcome Measure(s): Differential regulation of specific genes and gene expression signatures. Result(s): We identified 2,250 differentially expressed probe sets. One hundred twenty probe sets showed >2-fold change, of which 77 (64.2%) were up-regulated and 43 (35.8%) down-regulated. Genes involved in transcription were most overrepresented, with 43 out of 97 (44.3%) annotated probes, e.g., the transcription factor complex activator protein 1, including all three Jun genes (c-Jun, JunB, and JunD), two Fos genes (c-Fos and FosB), and activating transcription factor 3. In a Database for Annotation, Visualization, and Integrated Discovery analysis of the 2,007 down-regulated probe sets, proteins of the ribosome pathway and of two pathways involved in protein degradation, i.e., proteasome- and ubiquitin-mediated proteolysis, were significantly down-regulated. We identified eight breast cancer–associated gene expression signatures significantly overlapping with differentially regulated probe sets after cross-sex HT. Conclusion(s): Cross-sex HT in FtM transsexuals leads to the up-regulation and down-regulation of 243 and 2,007 distinct genes, respectively, and is associated with breast cancer–related gene expression signatures. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Prohibitin is an important antiproliferative protein inhibiting cell proliferation by blocking the G1/S transition of the cell cycle. Recent findings indicate that the presence of at least one mutant allele within a certain prohibitin gene polymorphism causes inactivation of bioactive RNA resulting in the loss of its pro-apoptotic function and a subsequent risk for malignant growth. Based on these findings we studied whether the presence of this prohibitin polymorphism increases the risk and worsens the prognosis of ovarian cancer in Caucasian women. Study design: A polymorphism within the 3′ untranslated region (UTR) of the prohibitin gene was evaluated by pyrosequencing in 136 Caucasian patients with epithelial ovarian cancer and 129 healthy Caucasian controls. Results: The wild-type C/C, heterozygous C/T, and the mutant T/T prohibitin genotype was found in 88 (64.7%), 46 (33.8%), and 2 (1.5%) patients with ovarian cancer and in 84 (65.1%), 39 (30.2%), and 6 (4.7%) healthy controls. Presence of at least one mutant allele of the prohibitin 3′ UTR polymorphism was not associated with an increased risk of ovarian cancer as compared to healthy controls (P =0.9). No association was found between presence of the prohibitin 3′ UTR polymorphism and the clinico-pathological parameters tumor stage, tumor grade, and patients’ age at diagnosis. Presence of at least one mutant allele of the prohibitin 3′ UTR polymorphism was not associated with disease-free and overall survival. Conclusion: The prohibitin 3′ UTR polymorphism was not associated with risk and prognosis of ovarian cancer in Caucasian women. [Copyright &y& Elsevier]

Abstract: Objective: To evaluate whether C-reactive protein (CRP) serum levels can be used as prognostic parameter in patients with vulvar cancer. Study design: CRP serum levels were measured at the time of first diagnosis of squamous cell vulvar cancer. Sixty-seven patients were enrolled; results were correlated to clinical data. Results: Mean CRP serum levels in patients with vulvar cancer were 0.8 (0.80)mg/dL. CRP serum levels were significantly associated with lymph node involvement (p =0.003), but not with tumor stage (p =0.03), histological grade (p =0.86) and patients’ age (p =0.64). Univariate analysis showed lymph node involvement, tumor stage and histological grade, but not CRP serum levels and patients’ age to be associated with overall survival. A multivariable analysis determined only lymph node involvement as independent prognostic parameter for disease-free interval and overall survival. Conclusion: CRP serum levels are closely associated with lymph node status but cannot be used as prognostic parameter in patients with vulvar cancer. [Copyright &y& Elsevier]

Abstract: Background: To investigate the clinical impact of MRI based cervix cancer brachytherapy combined with external beam radiochemotherapy applying dose volume adaptation and dose escalation in a consecutive group of patients with locally advanced cervix cancer. Methods: In the period 1998–2003, 145 patients with cervix cancer stages IB–IVA were treated with definitive radiotherapy +/− cisplatin chemotherapy. Median age was 60 years. In 67 patients, the tumour size was 2–5cm, in 78 patients it was >5cm. In 29 cases the standard intracavitary technique was combined with interstitial brachytherapy. Total prescribed dose was 80–85Gy (total biologically equivalent dose in 2Gy fractions). Since 2001, MRI based treatment planning integrated systematic concepts for High Risk Clinical Target Volume (HR CTV) and organs at risk (OAR), biological modelling, Dose–Volume–Histogram analysis, dose–volume–adaptation (D90, D 2cm3), and dose escalation, if appropriate and feasible. Findings: Dose volume adaptation was performed in 130/145 patients. The mean D90 during the whole period was 86Gy, with a mean D90 of 81Gy and 90Gy during the first and second period, respectively (p ≪0.01). Median follow-up was 51 months. Complete remission at 3 months was achieved in 138/145 patients (95%). Actuarial continuous complete remission for true pelvis (CCRtp) was 88% at 3 years. For tumours 2–5cm, CCRtp was 96% both in 1998–2000 and 2001–2003. For tumours >5cm it was 71% in 1998–2000 and 90% in 2001–2003 (p =0.05). Progression free survival (PFS) for true pelvis (local control) was 85%, PFS for distant metastases was 80%, both at 3 years. Local control for tumours >5cm was 64% in 1998–2000 and 82% in 2001–2003 (p =0.09) and 100% and 96%, respectively, for tumours 2–5cm. PFS for distant metastases remained the same during the two treatment periods with 79% and 80%. Overall survival (OS) was 58%, and cancer-specific survival (CSS) was 68% at 3 years. In the two different periods improvement in OS was from 53% to 64% (p =0.03) and in CSS from 62% to 74% (p =0.13). Improvement occurred only in tumours >5cm: OS 28% versus 58% (p =0.003); CSS 40% versus 62% (p =0.07). Actuarial late morbidity rate (LENT SOMA, grades 3 and 4) at 3 years was gastrointestinal 4%, urinary 4% and vaginal 5% (stage IIA/IIIA). Gastrointestinal and urinary late morbidity (G3,G4) was 10% in 1998–2000 and 2% in 2001–2003. Interpretation: In locally advanced extensive cervix cancer, local control of ⩾85% can be achieved with low treatment related morbidity (G3/G4), when exploiting the potential of MRI based 3D treatment planning including dose volume adaptation and dose escalation and a combined intracavitary/interstitial brachytherapy, if appropriate. A significant impact of this improvement of local control on survival is to be expected. For locally advanced limited disease the MRI based approach will likely result in assuring excellent local control (⩾95%) and in minimizing treatment related morbidity. [Copyright &y& Elsevier]

Abstract: Objective: To determine whether the cyclooxygenase (COX)-2 inhibitor rofecoxib increases the regression rates of cervical intraepithelial neoplasia (CIN) grade II and III. Study design: A prospective, randomized, placebo-controlled, double-blind study with rofecoxib 25mg daily for six months as active treatment for patients with CIN II and III was started in May 2005 and was halted after rofecoxib withdrawal in October 2005. Results: A total of 16 patients with CIN II (n =9) and CIN III (n =7) were included in our study. Eight and eight patients received rofecoxib and placebo, respectively. Regression rates in the rofecoxib and placebo arm were statistically not significant (25% versus 12.5%) after a mean of 87 (46.3) days of treatment. No severe side effects were noted during the therapy; no dropouts were recorded. Conclusion: A conservative treatment of CIN II and III is feasible. Inhibitors of COX, especially COX-2, were seen as candidates for cancer chemoprevention. Our study was halted after rofecoxib was withdrawn. The results obtained should be added to those already published for planning future studies on medical therapies for high grade CIN. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

Objective: To develop a model to predict the age at natural menopause and the risk for premenopausal hysterectomy.Design: Cross-sectional study.Setting: Multicenter study.Patient(s): A total of 1,345 white women.Intervention(s): Ten single nucleotide polymorphisms (SNPs) of seven estrogen (E)-metabolizing genes (i.e., catechol-O-methyltransferase, 17-beta-hydroxysteroid dehydrogenase type 1, cytochrome P-450 [CYP] 17, CYP1A1, CYP1B1, CYP19, and E receptor [ER] alpha) were analyzed by sequencing-on-chip-technology.Main Outcome Measure(s): Patients' reproductive and medical histories were ascertained and correlated to genotypes.Result(s): The model incorporates the number of full term pregnancies, the body mass index (BMI), a history of breast surgery, and the presence of CYP17 and CYP1B1-4 polymorphisms as well as the BMI to predict age at natural menopause and the risk for undergoing premenopausal hysterectomy.Conclusion(s): We present the first model to date, which can predict age at natural menopause and the risk for undergoing premenopausal hysterectomy based on genotype information and personal history. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]