Complete chorioamniotic membrane separation with constrictive amniotic band sequence and partial extra-amniotic pregnancy: serial ultrasound documentation and successful fetoscopic intervention.

Chorioamniotic membrane separation (CMS) comprises cases of spontaneous and iatrogenic detachment between the amniotic and chorionic membranes, with various fetal outcomes due to possible complications, particularly the formation of constrictive amniotic bands and preterm rupture of membranes. In the absence of mandatory management standards conservative monitoring is the most reported approach. In the case we present here, close sonographic surveillance afforded us the opportunity to observe the process from CMS to amnion rupture with the formation of constrictive amniotic bands and threatened cord impairment via constrictive margins of the amniotic sac. Despite the complicated background of reduced membranous layers in ruptured CMS, we performed a successful fetoscopic intervention with band release at 24 weeks' gestation and the pregnancy was prolonged to 34 weeks under close monitoring.

Prevalence of paternal perinatal depressiveness and its link to partnership satisfaction and birth concerns.

Depressive disorders have shown an increasing prevalence over the past decades. Growing evidence suggests that pregnancy and childbirth trigger depressive symptoms not only in women but likewise in men. This study estimates the prevalence of paternal perinatal depressiveness in a German community sample and explores its link to partnership satisfaction as well as birth-related concerns and concerns about the future. Data was gathered in a longitudinal study over the second and third trimester of their partner's pregnancy up to 6 weeks postpartum. In a two-stage screening procedure, 102 expectant fathers were assessed for symptoms of depression, anxiety, and partnership satisfaction using the Edinburgh Postnatal depression Scale (EPDS), the State/Trait Anxiety Inventory, a self-constructed questionnaire for birth concerns and the Questionnaire of Partnership. The prevalence of elevated depressive symptoms among expectant fathers was 9.8 % prenatally and 7.8 % postnatally. Prenatal relationship quality, prenatal EPDS scores, and birth concerns were significantly associated with and explained 47 % of the variance in paternal postnatal depressive symptoms. The prevalence of paternal depressive symptoms is a significant concern. Our findings point out the need for implementing awareness and screening for depressiveness in fathers in clinical routine in Germany as well as the necessity of developing a screening instrument for paternal birth-related anxiety.

The influence of general anxiety and childbirth-specific anxiety on birth outcome.

In the present study, we examined a German sample to determine whether anxiety symptoms during pregnancy had an impact on the duration and method of childbirth. Data of N = 88 women recruited at the Heidelberg University Hospital were used in the analyses. Prepartum anxiety symptoms were assessed with the State-Trait Anxiety Inventory (STAI, general anxiety) and the Pregnancy Related Anxiety Questionnaire (PRAQ-R, pregnancy-specific anxiety). Obstetric outcome was taken from birth records and operationalized by two parameters: the total duration of birth (dilation and fetal expulsion) and the incidence of pregnancy or birth-related interventions (ventouse, planned, and unplanned Cesarean section). The data show that childbirth-specific anxiety assessed by the PRAQ-R is an important predictor of total birth duration. In contrast, general anxiety measured by the STAI had no effect. The incidence of birth intervention was explained by parity. Anxiety, however, had no predictive value. In addition to medical factors, childbirth-specific anxiety during pregnancy plays an important role in the process of childbirth. The findings of the present study point to the need of implementing psychological interventions to reduce childbirth-specific anxiety and thereby positively influencing birth outcome.

Phase I study of apoptosis gene modulation with oblimersen within preoperative chemotherapy in patients with primary breast cancer.

Expression of the Bcl-2 protein confers resistance to chemotherapy-mediated apoptotic signals in patients with breast cancer. We investigated effects of Bcl-2 down-regulation by the Bcl-2 antisense oligodeoxynucleotide oblimersen in breast tumor biopsies. Oblimersen targets Bcl-2 messenger RNA (mRNA), down-regulates Bcl-2 protein translation and enhances antitumor effects of subtherapeutic chemotherapy doses. Within a phase I trial, we administered escalating doses of oblimersen (3, 5 or 7 mg/kg/day) as continuous infusion on days 1-7 in combination with standard-dose docetaxel (Taxotere), Adriamycin and cyclophosphamide (TAC) on day 5 as preoperative chemotherapy in 28 patients with T2-4 tumors. Effects of oblimersen were evaluated in tumor biopsies and peripheral blood mononuclear cells (PBMCs) 4 days after start of oblimersen and before TAC treatment by quantitative microfluidic real-time PCR. Read-outs consisted in measurement of Bcl-2 mRNA modulations and of 18 putative predictive markers. Two of 13 patients showed a diminution of Bcl-2 transcripts after 4 days of treatment with oblimersen 5 mg/kg/day. PBMCs could not be evaluated as a surrogate tissue because no qualified RNA could be isolated. Nevertheless, we demonstrated feasibility to process clinical samples and to obtain good quality RNA from tumor biopsies and indicated the potential of oblimersen to lower Bcl-2 mRNA in breast cancer.

[Hereditary breast cancer]. / Hereditäres Mammakarzinom.

Ten per cent of all breast cancer cases have a strong hereditary component in which half carry a deleterious mutation in the high penetrance genes BRCA1 or BRCA2. These genes confer a lifetime risk of 60-80% for breast cancer and 20-40% for ovarian cancer. Since the identification of these genes in the mid-1990s, an interdisciplinary approach was established in 12 specialized university-based centres in Germany for identifying high-risk families that enables genetic testing and preventive clinical options. It could be demonstrated that ultrasound, mammography, and breast MRI allow the identification of early breast cancer stages. Prophylactic mastectomy and salpingo-oophorectomy reduce breast and ovarian cancer incidence considerably. New therapeutic and preventive strategies are being validated in ongoing clinical studies. Most recently a new molecular target, a PARP inhibitor, was developed that targets specifically BRCA-deficient tumour cells. Participation in a phase II study for metastatic breast and ovarian cancer is available through the centres. Accompanying scientific studies of over 4,500 DNA samples from BRCA1/2-negative high-risk families are moreover being examined for other predisposing genes.

Oblimersen combined with docetaxel, adriamycin and cyclophosphamide as neo-adjuvant systemic treatment in primary breast cancer: final results of a multicentric phase I study.

BACKGROUND: Combining the Bcl-2 down-regulator oblimersen with cytotoxic treatment leads to synergistic antitumor effects in preclinical trials. This multicentric phase I study was carried out to evaluate maximum tolerated dose (MTD), safety and preliminary efficacy of oblimersen in combination with docetaxel, adriamycin and cyclophosphamide as neo-adjuvant systemic treatment (NST) in primary breast cancer (PBC). METHODS: Previously untreated patients with PBC T2-4a-c N0-3 M0 received one cycle of docetaxel 75 mg/m(2), adriamycin 50 mg/m(2) and cyclophosphamide 500 mg/m(2) administered on day 5 combined with escalating doses of oblimersen as a 24-h continuous infusion on days 1-7 followed by five cycles of combination of docetaxel, adriamycin and cyclophosphamide (TAC) without oblimersen every 3 weeks. Prophylactic antibiotic therapy and granulocyte colony-stimulating factor administration were used in all six cycles. Blood serum samples were taken throughout the treatment period for pharmacokinetic analysis. RESULTS: Twenty-eight patients were enrolled (median age, 50 years; ductal-invasive histology, 68%; tumorsize 2-5 cm, 61%; grade 3, 43%; hormone receptor negative, 36%; Her2 positive 18%) and received oblimersen in a dose of 3 mg/kg/day (cohort I, nine patients), 5 mg/kg/day (cohort II, nine patients) and 7 mg/kg/day (cohort III, 10 patients) respectively. No dose-limiting toxicity occurred. Following oblimersen combined with TAC, the most severe toxicity was neutropenia [National Cancer Institute-Common Toxicity Criteria (NCI-CTC) grades 1-2/3/4] which developed in 0/0/56% of patients (cohort I), 11/0/56% of patients (cohort II) and 20/20/50% of patients (cohort III). No febrile neutropenia occurred. Most common adverse events (all NCI-CTC grade < or = 2) were fatigue, nausea, alopecia, headache and flue-like symptoms observed in 78% (cohort I), 89% (cohort II) and 90% (cohort III) of patients. With increasing dose of oblimersen, a higher incidence of grade IV leukopenia and neutropenia was noted. At the MTD of 7 mg/kg/day of oblimersen, serious adverse events occurred in 40% of the patients. CONCLUSION: Oblimersen up to a dose of 7 mg/kg/day administered as a 24-h infusion on days 1-7 can be safely administered in combination with standard TAC on day 5 as NST in patients with PBC. The safety and preliminary efficacy warrants further evaluation of oblimersen in combination with every cycle of the TAC regimen in a randomized trial.

Prognostic significance of vascular endothelial growth factor expression in ovarian cancer patients: a long-term follow-up.

The purpose of the study was to determine vascular endothelial growth factor (VEGF) concentrations in ascites from ovarian cancer and to correlate these data with VEGF expression in ovarian tumors, serum VEGF concentrations, and clinicopathologic characteristics. Ascites, serum, and tumor tissue from 65 ovarian carcinomas and eight borderline tumors were collected. VEGF concentration in peritoneal fluids and sera was determined using enzyme immunoassay. VEGF tumor expression was evaluated immunohistochemically. Significantly higher VEGF concentrations were found in ascites from malignant tumors (median, 2575 pg mL(-1)) compared with borderline tumors (median 181.9 pg mL(-1)) and benign peritoneal fluid (184.5 pg mL(-1)). Both VEGF ascites concentration and tumor expression correlated with advanced tumor stages and ascites volume. Elevated VEGF ascites levels were negatively correlated to patient survival. No differences between VEGF serum levels could be observed between ovarian cancer patients and patients with benign cysts. This study showed for the first time the clinical significance of elevated VEGF ascites level in ovarian carcinomas. VEGF is expressed by ovarian tumor cells and locally released in the malignant peritoneal fluid but is not increased in the serum of preoperative ovarian cancer patients. The enhanced VEGF level support novel therapeutic perspectives by VEGF inhibition.

The K-ras mutation pattern in pancreatic ductal adenocarcinoma usually is identical to that in associated normal, hyperplastic, and metaplastic ductal epithelium.

BACKGROUND: Hyperplastic ductal lesions of the pancreas are believed to represent precursors of ductal adenocarcinoma. The most frequent mutation in manifest ductal carcinoma of the pancreas is the K-ras mutation at codon 12. The frequency and significance of this mutation in precursor lesions are a matter of controversy. METHODS: The study included 35 resection specimens of ductal adenocarcinoma of the head of the pancreas and 3 noncancerous, noninflammatory pancreases. Ductal lesions were classified according to established criteria. Single cells from these lesions were microdissected and analyzed by the denaturing gradient gel electrophoresis polymerase chain reaction method. RESULTS: All primary adenocarcinomas showed a K-ras mutation at codon 12 (25 cases with GAT, 7 cases with GTT, and 3 cases with CGT). One hundred and six of 364 ductal lesions were positive for the mutation. The highest relative percentage (53%) occurred in adenomatoid hyperplasia, followed by 36% in papillary hyperplasia, 26% in mucinous hypertrophy, and 14% in squamous metaplasia. With only two exceptions the mutation pattern of the ductal lesions and that of the corresponding primary tumor were identical. Twenty-one samples from normal ducts (17%) also harbored the K-ras mutation, as did 3 lesions from noncancerous specimens. CONCLUSIONS: K-ras mutations are common events in normal, hyperplastic, metaplastic, and neoplastic pancreatic ductal cells. Because K-ras mutations frequently, although not exclusively, are related to mucinous differentiation of pancreatic cells, this mutation may not cause but only promote mucinous differentiation. The prevalence of a certain mutation pattern in nonneoplastic and neoplastic ductal cells in an individual pancreas suggests the dominance of one carcinogenic factor.