Polymorphism 1558 C > T in the aromatase gene (CYP19A1) in low-grade endometrial stromal sarcoma.

Low-grade endometrial stromal sacomas (ESS) are estrogen-sensitive tumors. Polymorphic variation in the CYP19 gene can affect estrogen synthesis by increasing aromatase activity resulting in elevated levels of estrone and estradiol. We examined the polymorphism 1558 C > T in he aromatase gene (CYP19A1) in a series of 20 low-grade endometrial stromal sarcomas. Archival formalinfixed and paraffin-embedded material was analyzed with a fast real-time PCR system. The homozygous C/T- and the homozygous mutant T/T-genotypes were detected in 10/20 (50%) and 7/20 (35%) samples, respectively. Polymorphism 1558 C > T in the aromatase gene may represent a high-risk allele with increased local estrogen levels.

The impact of lymph node density on survival of cervical cancer patients.

BACKGROUND: To evaluate the prognostic value of lymph node density (LND) in patients with lymph node-positive cervical cancer. METHODS: A total of 88 consecutive patients were included in our study. Patients were treated with cisplatin-based concomitant chemoradiotherapy after surgical staging was performed at the Medical University of Vienna. Lymph node density, that is, the ratio of positive lymph nodes to the total number of lymph nodes removed, was assessed pathologically. Patients were stratified into two groups according to LND: patients with LND 10%. Lymph node density was correlated with clinicopathological parameters by chi(2)-tests. Univariate log-rank tests and multivariate Cox regression models were used to evaluate the association between LND and survival. RESULTS: A significant correlation between LND and FIGO stage (P=0.03), but not patients' age (P=0.2), histological grade (P=0.8), and histological type (P=0.5), was observed. In a univariate survival analysis, LND (P=0.01; P=0.01), FIGO stage (P=0.01; P=0.008), and histological grade (P=0.03; P=0.04) were associated with disease-free and overall survival, respectively. Patients with LND >10% had impaired disease-free and overall survival rates compared with patients with LND 10% is associated with an impaired disease-free and overall survival. Lymph node density may be used as an independent prognostic parameter in patients with lymph node-positive cervical cancer.

The prognostic value of plasma fibrinogen levels in patients with endometrial cancer: a multi-centre trial.

BACKGROUND: To analyse the correlation between pre-treatment plasma fibrinogen levels and clinical-pathological parameters in patients with endometrial cancer and to assess the value of plasma fibrinogen as a prognostic parameter. METHODS: Within a retrospective multi-centre study, the records of 436 patients with endometrial cancer were reviewed and pre-treatment plasma fibrinogen levels were correlated with clinical-pathological parameters and patients' survival. RESULTS: The mean (s.d.) pre-treatment plasma fibrinogen level was 388.9 (102.4) mg per 100 ml. Higher plasma fibrinogen levels were associated with advanced tumour stage (FIGO I vs II vs III and IV, P=0.002), unfavourable histological subtype (endometrioid vs non-endometrioid histology, P=0.03), and higher patients' age (< or =67 years vs >67 years, P=0.04), but not with higher histological grade (G1 vs G2 vs G3, P=0.2). In a multivariate analysis, tumour stage (P<0.001 and P<0.001), histological grade (P=0.009 and P=0.002), patients' age (P=0.001 and P<0.001), and pre-treatment plasma fibrinogen levels (P=0.04 and P=0.02) were associated with disease-free and overall survival, respectively. CONCLUSION: Plasma fibrinogen levels can be used as an independent prognostic parameter for the disease-free and overall survival of patients with endometrial cancer.

Monthly itraconazole versus classic homeopathy for the treatment of recurrent vulvovaginal candidiasis: a randomised trial.

OBJECTIVE: Antimycotics effectively treat sporadic and recurrent vulvovaginal candidiasis (RVVC). Classic homeopathy (CH) is also used to treat this condition. We compared the efficacy of CH and itraconazole in reducing the frequency of RVVC episodes. DESIGN: Single-centre, prospective, randomised trial. SAMPLE: One hundred-and-fifty patients with a history of RVVC and an acute episode of VVC. METHODS: Women were randomised into 3 groups: itraconazole with lactobacilli (group 1), itraconazole without lactobacilli (group 2) and CH (group 3). Itraconazole treatment of acute infection was followed by a 6-month maintenance regimen with monthly single-day itraconazole (200 mg bid). Women in group 1 were given additional vaginal lactobacilli for 6 days per month throughout the maintenance regimen Thereafter, patients were followed without treatment for 6 months. CH treatment was performed for 12 months. RESULTS: Women in groups 1 and 2 reached a culture-free status significantly earlier than women in group 3 (log-rank test; P < 0.0001). Specifically, before the start of the maintenance regimen, 44 of 49 women (89.8%) in group 1 and 40 of 47 women (85%) in group 2 were free of Candida detectable by culture, 22 of 46 (47%) women in group 3 reached a culture-free status after the first visit, but had a recurrence significantly earlier compared with women in groups 1 and 2 (log-rank test; P = 0.002). After 12 months, 19 of 25 (76%) women in group 1, 18 of 23 (78%) women in group 2 and 9 of 23 (39%) women in group 3 were free of culture-detectable Candida. Assessment of RVVC-associated complaints by VAS score showed that women in group 3 had a significantly higher level of discomfort (36.8, 25.1 and 27.7 respectively; P < 0.001) and were significantly less satisfied (59.2, 68.2 and 71.7 respectively; P < 0.001) than patients in groups 1 and 2. CONCLUSIONS: Monthly cycle-dependent itraconazole is more effective than CH in the treatment of RVVC. Lactobacilli do not confer an added benefit.

Gestational and Non-gestational Trophoblastic Disease. Guideline of the DGGG, OEGGG and SGGG (S2k Level, AWMF Registry No. 032/049, December 2015).

Purpose: The aim was to establish an official interdisciplinary guideline, published and coordinated by the German Society of Gynecology and Obstetrics (DGGG). The guideline was developed for use in German-speaking countries. In addition to the Germany Society of Gynecology and Obstetrics, the guideline has also been approved by the Swiss Society of Gynecology and Obstetrics (SGGG) and the Austrian Society of Gynecology and Obstetrics (OEGGG). The aim was to standardize diagnostic procedures and the management of gestational and non-gestational trophoblastic disease in accordance with the principles of evidence-based medicine, drawing on the current literature and the experience of the colleagues involved in compiling the guideline. Methods: This s2k guideline represents the consensus of a representative panel of experts with a range of different professional backgrounds commissioned by the DGGG. Following a review of the international literature and international guidelines on trophoblastic tumors, a structural consensus was achieved in a formalized, multi-step procedure. This was done using uniform definitions, objective assessments, and standardized management protocols. Recommendations: The recommendations of the guideline cover the epidemiology, classification and staging of trophoblastic tumors; the measurement of human chorionic gonadotropin (hCG) levels in serum, and the diagnosis, management, and follow-up of villous trophoblastic tumors (e.g., partial mole, hydatidiform mole, invasive mole) and non-villous trophoblastic tumors (placental site nodule, exaggerated placental site, placental site tumor, epitheloid trophoblastic tumor, and choriocarcinoma).

CD44v6 as a prognostic factor in cervical carcinoma FIGO stage IB.

The aim of our study was to clarify whether CD44v6 evaluation can serve as a universally applicable prognostic factor in patients with FIGO stage IB cervical carcinoma. A retrospective study was performed on 178 FIGO stage IB (142 IB N0, 36 IB N1) radically operated cervical carcinoma patients. The expression of CD44v6 was investigated by immunohistochemistry (IHC). The prognostic significance of established prognostic factors and CD44v6 expression was analyzed by univariate and multivariate analyses. To test the reproducibility and to account for interobserver variability, all specimens were evaluated independently at two institutions. Two different IHC scoring systems, several cut-off levels for CD44v6 positivity and several statistical methods for IHC results evaluation were used. In a univariate analysis, the most significant prognostic factor for overall survival (OS) was lymph node status (p<0.001) followed by tumor volume, LVSI, GOG score (p<0.01) and a deep stromal invasion (p = 0.06). We found a strong correlation between CD44v6 expression and squamous cell carcinoma (SCC) (SCC vs. adenocarcinoma - p<0.001) and between CD44v6 expression and deep stromal invasion, LVSI and GOG score (p<0.05). The CD44v6 expression was not a statistically significant prognostic factor for OS in a univariate analysis (p=0.39 Vienna; p=0.54 Freiburg). In a multivariate analysis, the most significant prognostic factor for OS was lymph node status (p =0.002), followed by tumor diameter and LVSI (p<0.05). CD44v6 expression was not a statistically significant prognostic factor for OS or disease-free interval (DFI) independent of the scoring method used. In conclusion, we demonstrated that CD44v6 expression is associated with LVSI, deep stromal invasion and SCC, but has no prognostic influence on OS and DFI in a population of 178 women with FIGO stage IB cervical carcinoma.

Serum concentrations of vascular endothelial growth factor in vulvar cancer.

The aim of the present study was to evaluate serum concentrations of vascular endothelial growth factor (VEGF) in patients with vulvar cancer and healthy female controls with respect to correlation of VEGF with clinicopathological parameters and impact on the patients' prognosis. Serum concentrations of VEGF were measured using a commercially available ELISA. Results were correlated to clinical data. Median serum concentrations of VEGF in patients with vulvar cancer (n = 41) and healthy female controls (n = 130) were 260 (range, 33-1216) pg/ml and 216 (range, 0-777) pg/ml, respectively (Mann-Whitney U test, P = 0.048). Serum concentrations of VEGF significantly correlated with tumor stage (Mann-Whitney U test, P = 0.02) but not with histological grade (Mann-Whitney U test, P = 0.2). In a univariate analysis, elevated pretreatment serum concentrations of VEGF were significantly correlated with a shortened disease-free and overall survival (Wilcoxon test, P = 0.03; and Wilcoxon test, P = 0.04, respectively). A multivariate Cox regression model considering tumor stage and serum concentrations of VEGF revealed, however, that serum concentrations of VEGF did not confer additional prognostic information to that already obtained by the established prognosticator tumor stage (multivariate Cox regression model: P = 0.9 and P = 0.8, respectively). Our data indicate that angiogenesis, as reflected by serum concentrations of VEGF, plays a functional role in vulvar carcinogenesis. VEGF seems to be a mediator of vulvar tumor growth but not of tumor cell dedifferentiation. Although associated with impaired disease-free and overall survival, pretreatment serum concentrations of VEGF are not an independent predictor of outcome in patients with vulvar cancer.

Modulation of IgA, IgE, and IgG Fc receptor expression on human mononuclear phagocytes by 1 alpha,25-dihydroxyvitamin D3 and cytokines.

The effects of 1 alpha,25-dihydroxyvitamin D3/calcitriol on the expression of Fc receptors (FcR) for IgA (Fc alpha R), IgE (Fc epsilon RII), and IgG (Fc gamma R) on human peripheral blood monocytes and the cell lines U937, THP-1, and Mono Mac-6, in combination with various cytokines, was examined by flow cytometry. On both monocyte-derived macrophages and the myelomonocytic cell lines, Fc alpha R/CD89 expression was induced by calcitriol alone and additively in combination with tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), and granulocyte-macrophage colony-stimulating factor. Constitutive and interleukin-4 (IL-4)-driven Fc epsilon RII/CD23 expression was markedly diminished on calcitriol-treated U937 cells and monocytes. Fc epsilon RII was also triggered by IFN-gamma, TNF-alpha, and IL-6 on all the cell lines, an effect blocked by calcitriol. On monocytes, the basal level and IFN-gamma-induced Fc gamma RI/CD64 expression was down-regulated by calcitriol and IL-4. The expression of Fc gamma RII/CD32 on monocytes was strongly suppressed by calcitriol. Transforming growth factor-beta induced Fc gamma RIII/CD16 on monocytes, an effect opposed by calcitriol. The ability of calcitriol-treated monocytes to phagocytose IgG-sensitized ox erythrocytes was diminished. Our results demonstrate that calcitriol, alone or in combination with cytokines, modulates Fc alpha R, Fc epsilon RII, Fc gamma RI, and Fc gamma RII expression on human mononuclear phagocytes, as well as Fc gamma R-mediated phagocytosis.

Progression or Regression? - Strengths and Weaknesses of the New Munich Nomenclature III for Cervix Cytology.

Introduction: Since 01. 01. 2015 the new Munich nomenclature III for gynaecological diagnostics of the cervix has been in force. The changes have led to controversial scientific discussions. This study reports for the first time on the consequences. Materials and Methods: The present data are based on smear screening results for the year 2014. The data of 63 134 patients were evaluated. Results: 2.27 % of all smears were remarkable. Group IIa was assigned to 0.91 %. Group II-p was somewhat more frequently recorded than group IIID1 (0.59 vs. 0.53 %). Groups IIID1 and IIID2 were found in 0.53 and 0.61 %, respectively, of the cases. Agreement with histology was found in 36.84 and 44.68 %, respectively. Glandular lesions represented the most frequent changes in group III. Histological clarification was obtained for 0.18 % of all remarkable findings. The relative incidence of high-grade precancerous conditions (CIN III) and invasive tumours amounted to 0.1 %. Conclusion: A close communication between gynaecologists and cytologists is mandatory for the correct usage of the new nomenclature. The future annual statistics of the health insurances can now be analysed in more detail. A statistical classification of glandular epithelial changes is now also possible for the first time. The heterogeneous group IIa constitutes an unnecessary uncertainty for patients and physicians. The splitting of the group IIID does not appear to have any advantage for the further clinical management. Further studies are needed to show whether or not the classification can stand up to international comparisons.

Quality of life of patients with end-stage peritoneal metastasis treated with Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC).

BACKGROUND: Quality of Life (QoL) plays an important role in patients with peritoneal metastasis and is deteriorating continuously until death. Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) is an innovative palliative treatment of peritoneal metastasis. We present the first QoL results under PIPAC therapy. METHODS: Retrospective analysis of QLQ30 questionnaire results during repeated courses of PIPAC applications in palliative patients with pretreated peritoneal metastasis. RESULTS: 91 patients (M:F = 40:51, median age 64 (34-77) years) with 158 PIPAC applications were analyzed. 86% patients had previously received systemic chemotherapy. Peritoneal metastasis was advanced (Peritoneal Carcinomatosis Index I = 16 ± 10). At admission, only moderate impairment of functioning (62-83%) and symptom scores (17-47%) was observed. 48 patients received at least 2 PIPAC every 6 weeks. After PIPAC # 1, the global physical score deteriorated slightly (from 82% to 75%), but improved after PIPAC # 2 (up to 89%). Gastrointestinal symptoms (nausea/vomiting, constipation, diarrhoea, anorexia) remained stable under PIPAC therapy. CONCLUSIONS: Quality of life was relatively high in this group of patients with advanced, pretreated peritoneal metastasis, explaining their wish for further therapy. Functioning scores and disease-related symptoms were not altered for at least 3 months in the patients able to receive repeated PIPAC. Except for a transient moderate increase of pain scores, PIPAC did not cause therapy-related QoL deterioration, especially no gastrointestinal symptoms.

Gestational Trophoblastic Disorders: An Update in 2015.

Gestational trophoblastic diseases (GTD) are a group of pregnancy-related disorders representing rare human tumours. They encompass premalignant disorders including complete (CHM), partial hydatidiform mole (PHM), exaggerated placental site (EPS), and placental-site nodule (PSN) as well as malignant disorders (also known as "gestational trophoblastic neoplasia [GTN]") including invasive mole, choriocarcinoma (CC), placenta-site trophoblastic tumour (PSTT), and epitheloid trophoblastic tumours (ETT) (Fig. 1). Originally, GTD develop from abnormal proliferation of trophoblastic tissue and form botryoid arranged vesicles. Premalignant moles are usually treated by suction curettage while persistent and recurrent moles and malignant forms require systemic therapy with methotrexate or combination chemotherapy consisting of etoposide, actimomycin D, methotrexate, vincristine, and cyclophosphamide (EMA-CO). ß-human chorion gonadotropin (ß-hCG) plays a crucial role in diagnosis and monitoring therapeutic effects. Since the definitive diagnosis cannot be obtained by histology in most cases, persistent or recurrent disease is diagnosed by elevated or persistent serum levels of ß-hCG. While curing rates are described to be as high as 98 %, GTD may initially present, recur, or end up as a metastasising systemic disease. This underlines the importance of a regular and consistent follow-up after treatment.

Recurrent Miscarriage: Diagnostic and Therapeutic Procedures. Guideline of the DGGG (S1-Level, AWMF Registry No. 015/050, December 2013).

Purpose: Official guideline coordinated and published by the German Society of Gynecology and Obstetrics (DGGG). Aim of the guideline was to standardize the diagnosis and treatment of patients with recurrent miscarriage (RM). Recommendations were proposed, based on the current national and international literature and the experience of the involved physicians. Consistent definitions, objective assessments and standardized therapy were applied. Methods: Members of the different involved societies developed a consensus in an informal process based on the current literature. The consensus was subsequently approved by the heads of the scientific societies. Recommendations: Recommendations for the diagnosis and treatment of patients with RM were compiled which took the importance of established risk factors such as chromosomal, anatomical, endocrine, hemostatic, psychological, infectious and immunological disorders into consideration.

Prognostic value of CD44 splice variants in human stage III cervical cancer.

The expression of specific cell adhesion molecule CD44 isoforms (splice variants) has been shown to be associated with poor prognosis in human malignancies, such as breast cancer. We used three different variant exon sequence-specific murine monoclonal antibodies to epitopes encoded by exons v5, v6 or v7-v8 of human variant CD44, to study the expression of CD44 splice variants by immunohistochemistry in human stage III cervical cancer. We investigated 40 pretreatment punch biopsies of cervical cancer FIGO stage III. CD44 splice variants CD44v5, CD44v6 and CD44v7-8 were detected by means of immunohistochemistry in 90%, 55% and 25%, respectively. CD44 epitopes encoded by exon v5 were not correlated with prognosis. Expression of CD44 splice variants containing epitopes encoded by exon v6 were correlated with significantly poorer prognosis (Mantel test, P = 0.008). Five-year survival rates with or without CD44v6 expression were 20% versus 71%, respectively. Expression of CD44v7-8 was also correlated with significantly poorer overall survival (Mantel test, P = 0.02). Expression of CD44 splice variants containing epitopes encoded by exons v7-v8 and especially exon v6 is associated with significantly poorer prognosis in stage III cervical cancer patients.

Serum M3/M21 in cervical cancer patients.

Cytokeratins are polypeptides which constitute a subclass of intermediate filaments in epithelial cells. The serum tumour marker M3/M21 is based on monoclonal antibodies against the epitopes M3 and M21 of cytokeratin 18. In the present study, we measured M3/M21 serum levels in 50 patients with FIGO stage IB-IIB cervical cancer and in 50 control subjects using a two-site radiometric immunoassay directed against soluble fragments of cytokeratin 18. Median serum levels of M3/M21 in patients with cervical cancer and in normal controls were 70.6 U/ml (range 0-397.7) and 6.5 U/ml (range 0-205.2), respectively (Mann-Whitney U-test, P = 0.0001). Median serum levels of M3/M21 prior to therapy and 4 weeks after therapy were 104.2 U/ml (range 24.6-397.7) and 39.3 U/ml (range 0-234.7), respectively (Mann-Whitney U-test, P = 0.004). We found a significant correlation between elevated M3/M21 serum levels and metastatic disease in pelvic lymph nodes (Mann-Whitney U-test, P = 0.002). 24 patients relapsed after complete remission. In these patients, elevated M3/M21 serum levels before the detection of relapse by computed tomography was observed in 13 cases. Considering these preliminary results, further studies with an increased number of patients are justified to clarify the prognostic value and the monitoring abilities of M3/M21 in cervical cancer patients.

Prognostic value of immunohistochemically detected CD44 isoforms CD44v5, CD44v6 and CD44v7-8 in human breast cancer.

We investigated the expression of CD44 isoforms containing variant exons v5, v6 and v7-8 in 115 human breast cancer specimens by means of immunohistochemistry. CD44 isoforms CD44v5, CD44v6 and CD44v7-8 were detected in 56% (n = 64), 24% (n = 28) and 15% (n = 17), respectively. In 36 specimens of axillary lymph node metastasis, expression of CD44v5, CD44v6 and CD44v7-8 was found in 94% (n = 34), 92% (n = 33) and 89% (n = 32), respectively. Five year survival rates with or without CD44v5 and CD44v6 expression were 71% versus 86% (log-rank test, P = 0.02) and 62% versus 81% (log-rank test, P = 0.001), respectively. For disease-free survival, expression of CD44v5, CD44v6 and CD44v7-8 showed a prognostic impact (log-rank test, P = 0.004, P = 0.0001 and P = 0.0001, respectively). However, multivariate analysis revealed that all investigated CD44 isoforms failed to be independent predictors of the patient's outcome.

Serum interleukin 1 in ovarian cancer patients.

Interleukin-1 (IL-1) is a multifunctional cytokine playing a central role in the immune response and displaying direct cytotoxic activity in vitro. Serum IL-1 alpha and beta levels were measured by enzyme linked immunosorbent assay (ELISA) in 75 ovarian cancer patients, 30 patients with benign ovarian cysts and 50 healthy controls. Both serum IL-1 alpha and IL-1 beta levels were more often elevated in ovarian cancer patients compared with healthy controls (chi-square test, P < 0.001 and P < 0.001, respectively). Mean serum IL-1 alpha and beta levels decreased significantly after surgical intervention (paired t-test, P = 0.0001 and P = 0.0002, respectively). No correlation with histopathological parameters and overall and disease-free survival was found. These preliminary results indicate that serum levels of IL-1 alpha and beta represent a host defence reaction rather than an autonomous tumour cell production.

Serum CD44 splice variants in cervical cancer patients.

Aberrant expression of the cell adhesion molecule CD44 has been detected in human tumours and has been shown to be associated with metastasis and poor prognosis in human malignancies. We evaluated serum levels of different soluble CD44 molecules (CD44 standard form and CD44 splice variants v5 and v6) in cervical cancer patients stage IB to IIIB. Two-hundred three serum samples were analysed. Serum levels of CD44st and CD44v5 showed no significant correlation with the presence or absence of cervical cancer. The splice variant CD44v6 showed a mean concentration of 227.3 +/- 90.9 (minimum 71.4, maximum 543.9) ng/ml when tumour was present and a mean concentration of 198.7 +/- 135.4 (minimum 67.2, maximum 696.3) ng/ml in cases of complete remission (P-value = 0.0001). However, in this preliminary study the sensitivity/specificity characteristic of CD44v6 was poor.

Serum evaluation of basic fibroblast growth factor in cervical cancer patients.

We present the data of 105 serum samples from 20 patients suffering from cervical cancer. Mean serum levels of basic fibroblast growth factor (bFGF) in patients with or without tumor present were 31.3 +/- 32.1 (minimum 0, maximum 156.7) pg/ml and 4.8 +/- 6.8 (minimum 0, maximum 29.6) pg/ml, respectively (P = 0.0001). bFGF reached a sensitivity of 65.7% at a specificity of 91.5% when applying a cut-off level of 15 pg/ml. Four patients relapsed after complete remission. A continuous increase of bFGF serum levels before the clinical detection of relapse (lead time) was seen in two cases with a mean lead time of 4 months. Preoperative serum levels were not of prognostic value and showed no correlation with pelvic lymph node metastasis. These preliminary results indicate that in cervical cancer patients soluble bFGF may be useful in early detection of primary tumors, recurrences and monitoring of therapy.

Menstrual phase and breast cancer surgery: influence on clinical outcome or pitfall of statistical analysis?

The influence of menstrual status at the time of surgery on the prognosis of women suffering from breast cancer is still discussed controversially. In our patient collective, including 149 patients, we obtained statistically significant results for six different time intervals, indicating that patients who underwent surgery between 11 and 22 days after the last menstrual period (LMP) have a poorer outcome. Focusing on the effect of statistical data evaluation strategy we designed a simulation study to evaluate the amount of type I error (error of a false positive test result) in a multiple testing situation involving a cyclical covariate. Accordingly, we corrected the minimum P-values for the occurring type I error rates. After that correction all six previously significant P-values failed to achieve statistical significance. The impact of different statistical data evaluation strategies in a multiple testing situation is discussed.