[Cystocele and perineal ultrasound : Comparison of reliability and patient satisfaction]. / Zystozele und perinealer Ultraschall : Vergleich von Reliabilität und Patientenzufriedenheit.

BACKGROUND: Pelvic organ prolapse is a common medical finding. The use of perineal ultrasound for diagnosis of cystoceles is gaining in importance. OBJECTIVES: The purpose of this work was to test whether perineal ultrasound can be used to diagnose a cystocele before surgery and for follow-up examination. Furthermore, patient satisfaction during speculum examination and perineal ultrasound was compared. MATERIALS AND METHODS: 33 women with cystocele were examined before and after anterior colporrhaphy. Symptoms and satisfaction were documented with questionnaires. RESULTS: Ultrasound measurements of both examiners were correlated before and after colporrhaphy. Also, the degree of cystocele and ultrasound were correlated during Valsalva after surgery. There was no clear relation between typical symptoms of the cystocele and ultrasound measurements. The patient's comfort is higher during ultrasound than during speculum examination (r = 0.45; p = 0.04. t = 4,418; p < 0.01). CONCLUSION: The results of the perineal ultrasound are reproducible before and after colporrhaphy. Patients prefer ultrasound to the speculum examination. A sonographic scale of the cystocele would extend the use of perineal ultrasound.

Statement by the Kommission Ovar of the AGO: The New FIGO and WHO Classifications of Ovarian, Fallopian Tube and Primary Peritoneal Cancer.

More than 25 years after the last revision, in 2012 the FIGO Oncology Committee began revising the FIGO classification for staging ovarian, Fallopian tube and primary peritoneal cancers. The new classification has become effective with its publication at the beginning of 2014. Following recent findings on the pathogenesis of ovarian, Fallopian tube and primary peritoneal cancer and reflecting standard clinical practice, the three entities have now been classified uniformly. The histological subtype is included (high-grade serous - HGSC; low-grade serous - LGSC; mucinous - MC; clear cell - CCC; endometrioid - EC). Stages III and IV have been fundamentally changed: stage IIIA now refers to a localized tumor limited to the pelvis with (only) retroperitoneal lymph node metastasis (formerly classified as IIIC). Stage IV has been divided into IVA and IVB, with IVA defined as malignant pleural effusion and IVB as parenchymatous or extra-abdominal metastasis including inguinal and mediastinal lymph node metastasis as well as umbilical metastasis. A new WHO classification was published almost concurrently. The classification of serous tumors addresses the issue of the tubal carcinogenesis of serous ovarian cancer, even if no tubal precursor lesions are found for up to 30 % of serous high-grade cancers. The number of subgroups was reduced and subgroups now include only high-grade serous, low-grade serous, mucinous, seromucinous, endometrioid, clear cell and Brenner tumors. The category "transitional cell carcinomas" has been dropped and the classification "seromucinous tumors" has been newly added. More attention has been focused on the role of borderline tumors as a stage in the progression from benign to invasive lesions.

The new FIGO staging system for ovarian, fallopian tube, and primary peritoneal cancer.

INTRODUCTION: Recent molecular research has revolutionized the understanding of ovarian cancer. It is now non-controversial that the term ovarian cancer summarizes a heterogenous group of malignant epithelial tumors. Findings of large clinical trials investigating surgical and systemic therapeutic approaches have defined the most important prognostic parameters. Therefore, the oncology committee of FIGO, headed by the South African gynecologic oncologist Lynette Denny, took the effort to revise the FIGO classification of ovarian cancer that was implemented in 1988. MATERIAL AND METHODS: The recent publication of Jaime Prat describing the new FIGO classification is summarized. The major changes compared to the hitherto existing classification from 1988 are presented. RESULTS: The primary anatomy is now documented (ov for ovarian, ft for fallopian tube, p for peritoneal, X for not assessed). The histological subtype is also documented (HGSC for high-grade serous carcinoma, LGSC for low-grade serous carcinoma, MC for mucinous carcinoma, CCC for clear cell carcinoma, and EC for endometrioid carcinoma). There is no stage I peritoneal cancer. Stage IC is subdivided into intraoperative rupture (IC1), pre-operative rupture (IC2), and malignant ascites or peritoneal washings (IC3). Due to its anatomic position within the pelvis, metastasis to the sigmoid colon is considered stage II. Former stage IIC has been erased. Stage IIIA1 and IIIA2 have been defined for intra-pelvic tumor with metastasis to retro-peritoneal lymph nodes up to 1 cm (IIIA1) or larger than 1 cm (IIIA2). With this, some of the former stage IIIC cases become IIIA and some IIIB, respectively. Involvement of retroperitoneal lymph nodes must be proven cytologically or histologically. Stage IV has been subdivided into IVA (malignant pleural effusions) and IVB (parenchymal metastases and/or extra-abdominal metastases including tumors in inguinal lymph nodes or lymph nodes outside of the abdominal cavity, umbilical tumor deposit, and transmural bowel infiltration (with mucosal involvement). CONCLUSION: The new FIGO classification takes into account the recent findings on the origin, pathogenesis, and prognosis of different ovarian cancer subtypes, summarizes groups of tumors pragmatically, and implies a reproducible and stage-dependent therapeutical approach.

The heterogeneity of ovarian cancer.

Ovarian cancer carries the worst prognosis of all gynecological malignancies. This is mainly due to its resistance against commonly used cytostatic drugs as well as the lack of a screening method for its detection at an early stage. Both basic and translational research have shown over the past decades that ovarian cancer as a medical term includes several types of tumors with different phenotypes, molecular biology, etiology, tumor progression, and even different prognosis. In this issue of Archives of Gynecology and Obstetrics, J. Dietel presents a review article about novel findings of the etiopathogenesis of ovarian cancer and the role that fallopian tubes may play. He also outlines the implied clinical consequences. Here, we give a brief overview of the heterogeneity of ovarian cancer to introduce the topic.

Predictive value of HER2 serum levels in patients treated with lapatinib or trastuzumab -- a translational project in the neoadjuvant GeparQuinto trial.

BACKGROUND: We were able to demonstrate a predictive value of serum HER2 (sHER2) in patients receiving trastuzumab in the neoadjuvant GeparQuattro trial. However, the role of sHER2 in patients receiving neoadjuvant therapy (NT) with lapatinib is still unclear. METHODS: The neoadjuvant GeparQuinto trial compared trastuzumab vs lapatinib in addition to chemotherapy in HER2-positive primary breast cancer patients. The sHER2 levels were measured by enzyme-linked immunosorbant assay in 210 patients, of whom 109 (52%) patients received trastuzumab and 101 (48%) lapatinib at three different time points. RESULTS: Twenty-two percent of patients had elevated baseline sHER2 levels (>15 ng ml⁻¹). A decrease of sHER2 levels (>20%) in the trastuzumab and lapatinib-treated group during NT was seen in 44% and 24% of the patients, an increase of sHER2 levels (>20%) was seen in 6% and 41% of patients, respectively. Higher pre-chemotherapy sHER2 levels were associated with higher pathological complete remission (pCR) rates in the entire study cohort (OR 1.8, 95% CI 1.02-3.2, P=0.043). A decline of sHER2 levels (>20%) during NT was a predictor for pCR in the lapatinib-treated patient group (OR: 11.7, 95% CI 1.3-110, P=0.031). CONCLUSION: Results of this study demonstrate that sHER2 levels change differently during NT depending on the anti-HER2 treatment strategy. Elevated baseline sHER2 levels (>15 ng ml⁻¹) and a decrease of sHER2 levels (>20%) early after therapy initiation are both relevant criteria to predict response to lapatinib-based treatment.

Induction of human ß-defensins and psoriasin in vulvovaginal human papillomavirus-associated lesions.

BACKGROUND: Infections with a low-risk type of human papillomavirus (HPV) may lead to genital warts. HPV targets the basal cell layer of epithelial cells. The first line of defense is the innate immune system, which provides nonspecific protection against a variety of pathogens. The antimicrobial peptides (AMPs) α- and ß-defensins, cathelicidins, psoriasin, and RNase7 are central mediators. METHODS: The expression of various α- and ß-defensins, cathelicidin LL-37, psoriasin, and RNase7 was studied in biopsy samples from 35 patients with genital warts and 25 healthy women using quantitative real-time polymerase chain reaction and immunohistochemical analysis. RESULTS: We found a significantly higher expression of the ß-defensins hBD-1 (P = .03), hBD-2 (P < 0.01), and hBD-3 (P < .001), and psoriasin (P = .001) in condylomata acuminata, compared with normal controls. The RNA and protein levels of RNase7 did not differ between infected and uninfected samples (P = .55). The α-defensins HNP 1-3, HD5, and HD6 and the cathelicidin LL-37 were scarcely detectable in normal and infected tissue. CONCLUSIONS: The differing expression of AMPs in HPV-infected, compared with noninfected, vulvovaginal biopsy samples suggests that these peptides are important in the local immune response. Curiously, hBD-1 shows a significant induction whereas RNase7 does not, which suggests differing regulation of AMPs over the course of bacterial and viral infections.

Heterogeneous expression of serine protease inhibitor maspin in ovarian cancer.

UNLABELLED: Ovarian cancer (OC) is a disease with poor prognosis, and molecular markers are needed to improve understanding of disease progression and resultant treatment. Only limited data concerning the expression of maspin, a serine protease inhibitor, in ovarian cancer (OC) are available. This study investigates the prognostic value of maspin expression (ME) in various OC cell lines and clinical tissue specimens from OC patients. PATIENTS AND METHODS: Tumour purified mouse anti-human maspin monoclonal antibody was applied to tissue specimens from 87 OC patients. ME was recorded by an immunoreactive score, which was correlated with grading, stage, histopathological subtypes and overall survival. Additionally ME was evaluated in established ovarian cancer cell lines (HEY, SKOV3, OVCAR3/8) and paclitaxel- and docetaxel-resistant HEY cells by QRT-PCR. RESULTS: There was significant correlation between cytoplasmatic ME and overall survival (p<0.05). OC patients with high levels of ME had a median survival of 28 vs. 57 months for those with low levels. Significant differential ME was detected between benign, borderline ovarian lesions and OC, as well as among different tumour gradings. Normal ovarian epithelial cells expressed less maspin than ovarian cancer cells as measured by QRT-PCR. Docetaxel- and paclitaxel-resistant ovarian cell lines showed an even higher level of ME, suggesting an unfavourable role of ME in OC cell lines. CONCLUSION: Maspin is expressed differentially in OC, and low expression levels of maspin are correlated with a longer survival.

Lymphatic capillary hypoplasia in the skin of fetuses with increased nuchal translucency and Turner's syndrome: comparison with trisomies and controls.

Fetuses with Turner's syndrome or trisomies 21, 18 and 13 show excess of skin, which can be visualized by ultrasonography as increased nuchal translucency at 11-13(+6) weeks' gestation. The objective of this study was to gain insight in the development and distribution of blood vessels, lymphatic capillaries of the cutis and lymphatic collectors of the cutis and subcutis and to study developmental changes with increasing gestation. Immunofluorescence of cryosections with 10 specific antibodies was used to investigate the nuchal skin of three fetuses with Turner syndrome's and to differentiate lymphatics, lymph capillaries (FLT4, PTN 63, LYVE1, PROX1), blood vessels (KDR, CD 31, PDPN), blood clotting activity (von Willebrand factor), basement membranes and big vessels (Laminin, Collagen Type IV). The findings were compared with those in seven fetuses with trisomy 21 and two fetuses each with trisomies 18 or 13, respectively, as well as six normal controls. Immunoreactive receptors for vascular endothelial growth factors (FLT4) were decreased in lymphatic capillaries of the skin of Turner fetuses. Accordingly, LYVE1 was scarce and PROX1 staining was less intense in the dermis of Turner fetuses. Lymphatic collectors were, however, evenly stained. In normal fetuses and in those with trisomies, lymphatic capillaries were evenly distributed. We conclude that lymphatic capillary hypoplasia might be responsible for nuchal cystic hygroma in Turner syndrome. The biological basis for increased nuchal translucency in trisomies may however be different.

The value of laparoscopic surgery to stage gynecological cancers: present and future.

The laparoscopic management of gynecologic cancers has been discussed controversely since decades. Much progress has been achieved technically enabling an experienced endoscopic surgeon to perform most of the gynecologic oncologic procedures such as hysterectomy, omentectomy, pelvic and paraaortic lymph node dissection. Although the value of laparoscopy with respect to oncological safety and patient's outcome has not been shown in prospective randomized clinical trials, many studies with altogether thousands of patients have revealed the feasibility and also similar oncologic results of laparoscopy when compared to laparotomy. Therefore, the laparoscopic approach has become well accepted for certain oncological indications, especially when early stage cancer cases are treated. These indications are also subject to ongoing Phase III trials: The LACC001 trial compares Total Laparoscopic Radical Hysterectomy (TLRH) or total robotic radical hysterectomy with total abdominal radical hysterectomy (TARH) for the treatment of early stage cervical cancer. The GOG LAP 2 and also the LACE001 trial compare total laparoscopic hysterectomy (TLH) with total abdominal hysterectomy (TAH) for the treatment of early stage endometrial cancer, whereby bilateral salpingo-oophorectomy, pelvic and paraaortic lymph node dissection is performed according to tumor stage and grade. This review summarizes the current status of laparoscopy in gynecologic oncology based on the literature to date, the ongoing clinical trials, and the recommendations of the German Gynecologic Oncology Group (AGO).

[Operative and interventional therapy of fibroids]. / Operative und interventionelle Therapie des Uterus myomatosus.

Myomas are the most frequent benign, solid tumours of the female genital tract in women of reproductive age. These tumours are estrogen dependent and their incidence rises with increasing age. A large number are asymptomatic, while others often cause bleeding disturbances or displacement complaints. Increasingly more women with uterus myomatosus desire to have children at a later age. In addition, progressively more women with myoma conditional complaints who have finished their family planning wish to retain their uterus. While the trend towards preserving organs has increased with the spread of minimal-invasive endoscopic techniques, minimal invasive radiological and non-invasive techniques are still searching for a place in the wide spectrum of treatment available today.

[Benign and borderline tumors of the ovary]. / Benigne und Borderline-Tumoren des Ovars.

Alterations of the ovaries easily cause diagnostic uncertainty about relevance and consequence. Palpable or sonographic ovarian tumors are reason for various differential diagnoses. Therefore the clarification of ovarian lesions is one of the main duties in daily gynaecological practice. Although diagnostic procedures might be supplemented by CT-Scan or MRI techniques, classical bimanual examination and vaginal ultrasound scan will determine the diagnosis in most cases comparably accurate. The suspected diagnosis concerning benign or malignant lesions, should take the palpable and sonographic feature, as well as the information from the patients medical history (e.g. family history of malignant diseases (BRCA 1/2 mutations) into account. In this regard, there are no other additional parameters established. Serum tumormarkers (CA 12.5) or sonographic examinations (including Doppler) have low sensitivity and specificity. Clinical diagnostic experience seems to be crucial. Cystic lesions mostly occur in premenopausal women and commonly relapse. They are mostly normal follicle cysts, but may also be a tumor of low malignant potential (LMP-tumor) or even an invasive cancerous lesion. 20-30% of all ovarian tumors are malignant and by the time of primary diagnosis already in a about 60-70% incurable due to intraabdominal dissemination. Benign or malignant lesions may occur in every age group. Ovarian tumors at infantile age are malignant in about 15%. Most malignant tumors occur between the age of 50 to 70. The LMP-tumors occur in average 10 years earlier. Malignant ovarian lesions represent about 15-30% of all genital malignant tumors. Hormonal contraceptives, pregnancy and breast feeding seem to be protective. The persistence of ovarian cysts and tumors will be mostly examined by laparoscopic surgery. In that respect the diagnosis of LMP-tumors might be incidentally and will then have a substantial impact on the extent of the surgery and the follow up. This compilation overviews the spectrum of benign and low malignant potential tumors of the ovary and their different tissues of origin.

Glycosaminoglycans and proteoglycans in the skin of aneuploid fetuses with increased nuchal translucency.

BACKGROUND: First trimester increased fetal nuchal translucency is associated with fetal aneuploidies. One of the mechanisms of pathophysiology could be an abnormal extracellular matrix facilitating the formation of an interstitial edema. A previous study investigating interstitial edema in first trimester fetuses found large amounts of hyaluronan in the skin of fetuses with trisomy 21. The aim of this study was to establish distribution patterns for a number of other glycosaminoglycans-dermatan, heparan and keratan sulphate, chondroitin-6-sulphate and chondroitin-4-sulphate proteoglycan-in the nuchal skin of normal and chromosomally abnormal fetuses at 11-14 weeks. We also investigated whether biglycan (BGN), which is located on chromosome X, is underexpressed in fetuses with Turner syndrome. Decorin (DCN), a similar-sized proteoglycan located on chromosome 12, was taken as a control. METHODS: We studied the distribution and concentration of various extacellular matrix components using immunohistochemistry, a double staining technique, in-situ hybridization, Northern and Western blot analysis. RESULTS: Chondroitin-6-sulphate and chondroitin-4-sulphate proteoglycan were increased in Turner syndrome fetuses and BGN seemed to be underexpressed compared with normal controls, while DCN was not. Dermatan, heparan and keratan sulphate showed no significant abnormal distribution in trisomies 21, 18, 13, or in Turner syndrome, compared with normal. Western and immunohistochemical analysis revealed that absence of a second X chromosome, as is the case in Turner syndrome, affects BGN protein pattern. CONCLUSIONS: An abnormal amount of glycosaminoglycans and proteoglycans presumably contributes to increased nuchal translucency.

Expression and potential role of Fas-associated phosphatase-1 in ovarian cancer.

Fas-associated phosphatase-1 (FAP-1) is a protein-tyrosine phosphatase that binds the cytosolic tail of Fas (Apo1, CD95), presumably regulating Fas-induced apoptosis. Elevations of FAP-1 protein levels in some tumor cell lines have been correlated with resistance to Fas-induced apoptosis. To explore the expression of FAP-1 in ovarian cancer cell lines and archival tumor specimens, mouse monoclonal and rabbit polyclonal antibodies were generated against a FAP-1 peptide and recombinant FAP-1 protein. These antibodies were used for immunoblotting, immunohistochemistry, and flow-cytometry analysis of FAP-1 expression in the Fas-sensitive ovarian cancer lines HEY and BG-1, and in the Fas-resistant lines OVCAR-3 FR and SK-OV-3. All methods demonstrated high levels of FAP-1 in the resistant lines OVCAR-3 FR and SK-OV-3, but not in the Fas-sensitive lines HEY and BG-1. Furthermore, levels of FAP-1 protein also correlated with the amounts of FAP-1 mRNA, as determined by reverse transcriptase-polymerase chain reaction analysis. FAP-1 protein levels were investigated by immunoblotting in the National Cancer Institute's panel of 60 human tumor cell lines. Although FAP-1 failed to correlate with Fas-resistance across the entire tumor panel, Fas-resistance correlated significantly with FAP-1 expression (P: < or = 0.05) and a low Fas/FAP-1 ratio (P: < or = 0.028) in ovarian cancer cell lines. FAP-1 expression was also evaluated in 95 archival ovarian cancer specimens using tissue-microarray technology. FAP-1 was expressed in nearly all tumors, regardless of histological type or grade, stage, patient age, response to chemotherapy, or patient survival. We conclude that FAP-1 correlates significantly with Fas resistance in ovarian cancer cell lines and is commonly expressed in ovarian cancers.

Evaluation of methods to detect p53 mutations in ovarian cancer.

OBJECTIVE: The p53 status is increasingly regarded as a marker predictive of response to particular cancer therapies, but for this approach it is self-evident that the p53 status must be determined correctly. METHODS: We have tested ovarian cancers with single-strand conformation polymorphism analysis (SSCP), immunohistochemical staining with DO-1 anti-p53 antibody (IHC), and yeast p53 functional assay (FASAY). RESULTS: These techniques commonly used to detect p53 mutations showed important differences in their sensitivity. Of 53 tumors tested with three indirect techniques, 27 (50%), 33 (62%) and 41 (77%) were positive by SSCP, IHC, and FASAY, respectively. In a subset of 32 tumors strongly suspected of containing mutations, 25 (78%), 26 (81%), 29 (91%) and 30 (94%) were positive by SSCP, immunostaining, DNA sequencing and yeast assay, respectively. CONCLUSIONS: Under comparable routine conditions, the FASAY reached the highest sensitivity. Since no single technique detected all mutations, we recommend the use of at least two different techniques in situations where the p53 status will affect patient management.

Exposure of human endometrium to environmental estrogens, antiandrogens, and organochlorine compounds.

OBJECTIVE: To determine concentrations of environmental estrogens, antiandrogens, and organochlorine compounds in human endometrium and body fat. DESIGN: Cross-sectional, population-based study. SETTING: Patient recruitment was done at a university hospital; chemical analysis was performed in a specialized private laboratory. PATIENT(S): Premenopausal, unexposed women undergoing hysterectomy for uterine myoma. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Concentrations of environmental modulators in human endometrium and body fat were quantified by high-resolution gas chromatography/high-resolution mass spectrometry. RESULT(S): Among known endocrine modulators, the antiandrogenic p, p'-dichlorodiphenyl-dichloroethylene was found in the highest concentrations in endometrium (median 4.7 microg/kg wet weight) and body fat (median 446 microg/kg wet weight). Only trace amounts of the identified environmental estrogens beta-hexachlorocyclohexane, o, p'-dichlorodiphenyl-trichloroethane, bisphenol A, hydroxylated polychlorinated biphenyls, and genistein were found in the endometrium (median <1 microg/kg wet weight). As major organochlorine contaminants without endocrine activities, polychlorinated biphenyls and hexachlorobenzene were found. CONCLUSION(S): Our data demonstrate that nonchlorinated environmental estrogens do not build up cumulative tissue concentrations in the endometrium. The risk of reduced fertility because of ambient levels of environmental estrogens in the endometrium is negligible.

G-CSF receptor expression in ovarian cancer.

Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is clinically used to overcome neutropenic periods during chemotherapy. In vitro studies using cell lines as a model system have recently suggested that G-CSF can promote ovarian cancer growth. The objective of this work is to determine whether tumor cells express G-CSF-receptors (G-CSFR). A set of ovarian tumor biopsies and ovarian cancer cell lines was analyzed by RT-PCR, immunohistochemistry and immunofluorescence. The presence of a 276 bp-amplicon (exon 8-10) obtained by RT-PCR showed that 12 out of 16 ovarian tumor biopsies and two out of four ovarian cancer cell lines expressed G-CSFR-mRNA. G-CSFR-protein was detected in tumor cells of the 12 biopsies that also contained G-CSFR-mRNA. A second 409 bp-amplicon (exon 17) obtained by RT-PCR from the variable C-terminal cytoplasmic region of G-CSFR could be amplified only in four out of 16 biopsies and in none of the ovarian cancer cell lines studied. The results presented here indicate that G-CSFR is frequently expressed in ovarian cancer cells. Moreover, the failure of RT-PCR amplification of the 409 bp-amplicon in samples that express G-CSFR-mRNA suggests that C-terminal truncated receptor forms are also expressed.